Breast cancer laboratory tests: Difference between revisions

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VisualWikitext

Latest revision as of 14:40, 22 April 2019

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Soroush Seifirad, M.D.[2], Ammu Susheela, and Mirdula Sharma

Overview

Laboratory studies play a crucial role in prevention, diagnosis, staging, treatment planning, management, determining prognosis and follow up of patients with breast cancer. Among them are single gene studies (i. e. BRCA1, BRCA2, and HER2), multiple gene panels (i.e. Oncotype DX), tumor markers (Ki67), and metastatic markers such as serum alkaline phosphatase as a marker of bone metastasis. A variety of other blood chemistry tests are also used in the management process of patients with breast cancer, among them are liver function tests (alanine aminotransferase (ALT), aspartate transaminase (AST) , bilirubin, alkaline phosphatase) and markers of kidney function (BUN, creatinine).

HER2

HER2 is a member of the human epidermal growth factor receptor (HER/EGFR/ERBB) family.
Amplification or over-expression of this oncogene has been shown to play an important role in the development and progression of certain aggressive types of breast cancer.
In recent years the protein has become an important biomarker and target of therapy for approximately 30% of breast cancer patients.^[1] HER2 has several names among them are:

Receptor tyrosine-protein kinase erbB-2
CD340 (cluster of differentiation 340)
proto-oncogene Neu
Erbb2 (rodent), or ERBB2 (human)
HER2 (from human epidermal growth factor receptor 2)
HER2/neu ^[2]^[3]^[4]

Signaling pathways

Signaling pathways activated by HER2 include:^[5]

mitogen-activated protein kinase (MAPK)
phosphoinositide 3-kinase (PI3K/Akt)
phospholipase C γ
protein kinase C (PKC)
Signal transducer and activator of transcription (STAT)

In a nutshell, signaling through the ErbB family of receptors promotes cell proliferation and opposes apoptosis, and therefore must be tightly regulated to prevent uncontrolled cell growth from occurring.

Cancer biopsy

HER2 testing is performed in breast cancer patients to assess prognosis and to determine suitability for trastuzumab therapy.
Trastuzumab has been associated with cardiac toxicity.^[6]
Tests are usually performed on biopsy samples obtained by either fine-needle aspiration, core needle biopsy, vacuum-assisted breast biopsy, or surgical excision.
Immunohistochemistry is used to measure the amount of HER2 protein present in the sample.
Examples of this assay include HercepTest, Dako, Glostrup, and Denmark. T
he sample is given a score based on the cell membrane staining pattern. Specimens with equivocal IHC results should then be validated using fluorescence in situ hybridisation (FISH).
FISH can be used to measure the number of copies of the gene which are present and is thought to be more reliable than IHC.^[7]

**3D reconstruction of dual color acquistion of Her2/neu and Her 3.** A) conventional wide-field fluorescence image of an AG11132 mammary epithelial cells. Her3 is labelled with Alexa488 (green) and Her2/neu with Alexa568 (red). B) magnified image of a small area of A. C) localization microscopy SPDM of the same region of interest as in B. D) and E) show a 3D reconstruction of the protein clusters using the combination of SPDM and SMI microscopy (LIMON technology). Scale bars in D) and E) are 500 nm in each direction. Source:https://commons.wikimedia.org/wiki/File:3D_Dual_Color_Super_Resolution_Microscopy_Cremer_2010.png

Serum

The extracellular domain of HER2 can be shed from the surface of tumour cells and enter the circulation.
Measurement of serum HER2 by enzyme-linked immunosorbent assay (ELISA) offers a far less invasive method of determining HER2 status than a biopsy and consequently has been extensively investigated.
Results so far have suggested that changes in serum HER2 concentrations may be useful in predicting response to trastuzumab therapy.^[8]
However, its ability to determine eligibility for trastuzumab therapy is less clear.^[9]

Cancer

Amplification, also known as the over-expression of the ERBB2 gene, occurs in approximately 15-30% of breast cancers.^[1]^[10]
It is strongly associated with increased disease recurrence and a poor prognosis.^[11]
HER2 is colocalised and most of the time, coamplified with the gene GRB7, which is a proto-oncogene associated with breast, testicular germ cell, gastric, and eosophageal tumours.
HER2 proteins have been shown to form clusters in cell membranes that may play a role in tumorigenesis.^[12]^[13]
Recent evidence has implicated HER2 signaling in resistance to the EGFR-targeted cancer drug cetuximab.^[14]

Mutations

Furthermore, diverse structural alterations have been identified that cause ligand-independent firing of this receptor, doing so in the absence of receptor over-expression.
HER2 is found in a variety of tumours and some of these tumors carry point mutations in the sequence specifying the transmembrane domain of HER2.
Substitution of a valine for a glutamic acid in the transmembrane domain can result in the constitutive dimerization of this protein in the absence of a ligand.^[15]
HER2 mutations have been found in non-small-cell lung cancers (NSCLC) and can direct treatment.^[16]

As a drug target

HER2 is the target of the monoclonal antibody trastuzumab (marketed as Herceptin).
Trastuzumab is effective only in cancers where HER2 is over-expressed.
One year of trastuzumab therapy is recommended for all patients with HER2-positive breast cancer who are also receiving chemotherapy.^[17] Twelve months of trastuzumab therapy is optimal. Randomized trials have demonstrated no additional benefit beyond 12 months, whereas 6 months has been shown to be inferior to 12.
Trastuzumab is administered intravenously weekly or every 3 weeks.^[18]
An important downstream effect of trastuzumab binding to HER2 is an increase in p27, a protein that halts cell proliferation.^[19]
Another monoclonal antibody, Pertuzumab, which inhibits dimerisation of HER2 and HER3 receptors, was approved by the FDA for use in combination with trastuzumab in June 2012.
As of November 2015, there are a number of ongoing and recently completed clinical trials of novel targeted agents for HER2+ metastatic breast cancer, e.g. margetuximab.^[20]
Additionally, NeuVax (Galena Biopharma) is a peptide-based immunotherapy that directs "killer" T cells to target and destroy cancer cells that express HER2. It has entered phase 3 clinical trials.
It has been found that patients with ER+ (Estrogen receptor positive)/HER2+ compared with ER-/HER2+ breast cancers may actually benefit more from drugs that inhibit the PI3K/AKT molecular pathway.^[21]
Over-expression of HER2 can also be suppressed by the amplification of other genes. Research is currently being conducted to discover which genes may have this desired effect.
The expression of HER2 is regulated by signaling through eostrogen receptors.
Normally, estradiol and tamoxifen acting through the eostrogen receptor down-regulate the expression of HER2. However, when the ratio of the coactivator AIB-3 exceeds that of the corepressor PAX2, the expression of HER2 is upregulated in the presence of tamoxifen, leading to tamoxifen-resistant breast cancer.^[22]^[23]

Multiple gene panels

Oncotype DX®:

For small hormone receptor-positive tumors that have not spread to more than 3 lymph nodes
Also may be used for more advanced tumors
Might be used for DCIS (ductal carcinoma in situ or stage 0 breast cancer). as well looks at a set of 21 genes in tumor biopsy samples to get a “recurrence score,” which is a number between 0 and 100.
The score reflects the risk of breast cancer coming back (recurring) in the next 10 years and how likely you will benefit from getting chemo after surgery.
The lower the score (usually 0-10) the lower the risk of recurrence.
Benefit from chemotherapy is in doubt in most women with low scores
An intermediate score (usually 11-25): intermediate risk of recurrence.
Benefit from chemotherapy is in doubt in most women with intermediate-recurrence scores,
Nevertheless chemotherapy is believed to be beneficial for women younger than 50 with a higher intermediate score (16-25)
The possible risks and benefits of chemo should be weighted and discussed prior to decision making.
A high score (usually 26-100): higher risk of recurrence.Chemotherapy is recommended for women with high scores in order to help lower the chance of cancer *recurrence.
OncotypeDx is the only multigene panel with level I of evidence, and hence has been incorporated in the AJCC staging system

MammaPrint®:

To determine the likelihood of cancer recurrence in a distant part of the body after treatment.
May be used in any type of breast cancer with stage 1 or 2 that has spread to no more than 3 lymph nodes.
Hormone and HER2 status are also evaluated in this test. Seventy different genes are examined in this test to determine the 10 years cancer recurrence
The test results are reported as either “low risk” or “high risk.”
Unlike OncotypeDx has not been incorporated in the AJCC staging system yet.

BRCA1/BRCA2

BRCA1

The human BRCA1 gene is located on the long (q) arm of chromosome 17 at region 2 band 1, from base pair 41,196,312 to base pair 41,277,500 (Build GRCh37/hg19) (map).^[24]
BRCA1 orthologs have been identified in most vertebrates for which complete genome data are available ^[25].

Function and mechanism

BRCA1 is part of a complex that repairs double-strand breaks in DNA. Th
In the nucleus of many types of normal cells, the BRCA1 protein interacts with RAD51 during repair of DNA double-strand breaks.^[26]
These breaks can be caused by natural radiation or other exposures, but also occur when chromosomes exchange genetic material (homologous recombination, e.g., "crossing over" during meiosis). TBy influencing DNA damage repair, these three proteins play a role in maintaining the stability of the human genome.
BRCA1 is also involved in another type of DNA repair, termed mismatch repair.
BRCA1 interacts with the DNA mismatch repair protein MSH2.^[27]
MSH2, MSH6, PARP and some other proteins involved in single-strand repair are reported to be elevated in BRCA1-deficient mammary tumors.^[28]

A protein called valosin-containing protein (VCP, also known as p97) plays a role to recruit BRCA1 to the damaged DNA sites.
After ionizing radiation, VCP is recruited to DNA lesions and cooperates with the ubiquitin ligase RNF8 to orchestrate assembly of signaling complexes for efficient DSB repair.^[29]
BRCA1 interacts with VCP.^[30]
BRCA1 also interacts with c-Myc, and other proteins that are critical to maintain genome stability.^[31]

BRCA1 directly binds to DNA, with higher affinity for branched DNA structures. This ability to bind to DNA contributes to its ability to inhibit the nuclease activity of the MRN complex as well as the nuclease activity of Mre11 alone.^[32]
This may explain a role for BRCA1 to promote lower fidelity DNA repair by non-homologous end joining (NHEJ).^[33]
BRCA1 also colocalizes with γ-H2AX (histone H2AX phosphorylated on serine-139) in DNA double-strand break repair foci, indicating it may play a role in recruiting repair factors.^[34]^[35]

Formaldehyde and acetaldehyde are common environmental sources of DNA cross links that often require repairs mediated by BRCA1 containing pathways.^[36]^[37]

This DNA repair function is essential; mice with loss-of-function mutations in both BRCA1 alleles are not viable, and as of 2015 only two adults were known to have loss-of-function mutations in both alleles; both had congenital or developmental issues, and both had cancer. One was presumed to have survived to adulthood because one of the BRCA1 mutations was hypomorphic.^[38]

Certain variations of the BRCA1 gene lead to an increased risk for breast cancer as part of a hereditary breast-ovarian cancer syndrome.
Researchers have identified hundreds of mutations in the BRCA1 gene, many of which are associated with an increased risk of cancer.
Females with an abnormal BRCA1 or BRCA2 gene have up to an 80% risk of developing breast cancer by age 90; increased risk of developing ovarian cancer is about 55% for females with BRCA1 mutations and about 25% for females with BRCA2 mutations.^[39]

These mutations can be changes in one or a small number of DNA base pairs (the building-blocks of DNA), and can be identified with PCR and DNA sequencing.

In some cases, large segments of DNA are rearranged. Those large segments, also called large rearrangements, can be a deletion or a duplication of one or several exons in the gene.
Classical methods for mutation detection (sequencing) are unable to reveal these types of mutation.^[40]
Other methods have been proposed: traditional quantitative PCR,^[41] Multiplex Ligation-dependent Probe Amplification (MLPA),^[42] and Quantitative Multiplex PCR of Short Fluorescent Fragments (QMPSF).^[43]
Newer methods have also been recently proposed: heteroduplex analysis (HDA) by multi-capillary electrophoresis or also dedicated oligonucleotides array based on comparative genomic hybridization (array-CGH).^[44]

Some results suggest that hypermethylation of the BRCA1 promoter, which has been reported in some cancers, could be considered as an inactivating mechanism for BRCA1 expression.^[45]

A mutated BRCA1 gene usually makes a protein that does not function properly
. Researchers believe that the defective BRCA1 protein is unable to help fix DNA damage leading to mutations in other genes.
These mutations can accumulate and may allow cells to grow and divide uncontrollably to form a tumor. Thus, BRCA1 inactivating mutations lead to a predisposition for cancer.

BRCA1 mRNA 3' UTR can be bound by an miRNA, Mir-17 microRNA. It has been suggested that variations in this miRNA along with Mir-30 microRNA could confer susceptibility to breast cancer.^[46]

In addition to breast cancer, mutations in the BRCA1 gene also increase the risk of ovarian and prostate cancers. Moreover, precancerous lesions (dysplasia) within the Fallopian tube have been linked to BRCA1 gene mutations. Pathogenic mutations anywhere in a model pathway containing BRCA1 and BRCA2 greatly increase risks for a subset of leukemias and lymphomas.^[47]

Females who have inherited a defective BRCA1 or BRCA2 gene are at a greatly elevated risk to develop breast and ovarian cancer.
Their risk of developing breast and/or ovarian cancer is so high, and so specific to those cancers, that many mutation carriers choose to have prophylactic surgery.
There has been much conjecture to explain such apparently striking tissue specificity.
Major determinants of where BRCA1/2 hereditary cancers occur are related to tissue specificity of the cancer pathogen, the agent that causes chronic inflammation or the carcinogen.
The target tissue may have receptors for the pathogen, may become selectively exposed to an inflammatory process or to a carcinogen.
An innate genomic deficit in a tumor suppressor gene impairs normal responses and exacerbates the susceptibility to disease in organ targets.
This theory also fits data for several tumor suppressors beyond BRCA1 or BRCA2. A major advantage of this model is that it suggests there may be some options in addition to prophylactic surgery.^[48]

Low expression of BRCA1 in breast and ovarian cancers

BRCA1 expression is reduced or undetectable in the majority of high grade, ductal breast cancers.^[49]
It has long been noted that loss of BRCA1 activity, either by germ-line mutations or by down-regulation of gene expression, leads to tumor formation in specific target tissues.
In particular, decreased BRCA1 expression contributes to both sporadic and inherited breast tumor progression.^[50]
Reduced expression of BRCA1 is tumorigenic because it plays an important role in the repair of DNA damages, especially double-strand breaks, by the potentially error-free pathway of homologous recombination.^[51]
Since cells that lack the BRCA1 protein tend to repair DNA damages by alternative more error-prone mechanisms, the reduction or silencing of this protein generates mutations and gross chromosomal rearrangements that can lead to progression to breast cancer.^[51]

Similarly, BRCA1 expression is low in the majority (55%) of sporadic epithelial ovarian cancers (EOCs) where EOCs are the most common type of ovarian cancer, representing approximately 90% of ovarian cancers.^[52]
In serous ovarian carcinomas, a sub-category constituting about 2/3 of EOCs, low BRCA1 expression occurs in more than 50% of cases.^[53]
Bowtell^[54] reviewed the literature indicating that deficient homologous recombination repair caused by BRCA1 deficiency is tumorigenic.
In particular this deficiency initiates a cascade of molecular events that sculpt the evolution of high-grade serous ovarian cancer and dictate its response to therapy.
Especially noted was that BRCA1 deficiency could be the cause of tumorigenesis whether due to BRCA1 mutation or any other event that causes a deficiency of BRCA1 expression.

Mutation of BRCA1 in breast and ovarian cancer

Only about 3%–8% of all women with breast cancer carry a mutation in BRCA1 or BRCA2.^[55] Similarly, BRCA1 mutations are only seen in about 18% of ovarian cancers (13% germline mutations and 5% somatic mutations).^[56]

Thus, while BRCA1 expression is low in the majority of these cancers, BRCA1 mutation is not a major cause of reduced expression.

BRCA1 promoter hypermethylation in breast and ovarian cancer

BRCA1 promoter hypermethylation was present in only 13% of unselected primary breast carcinomas.^[57] Similarly, BRCA1 promoter hypermethylation was present in only 5% to 15% of EOC cases.^[52]

Thus, while BRCA1 expression is low in these cancers, BRCA1 promoter methylation is only a minor cause of reduced expression.

MicroRNA repression of BRCA1 in breast cancers

There are a number of specific microRNAs, when overexpressed, that directly reduce expression of specific DNA repair proteins (see MicroRNA section DNA repair and cancer) In the case of breast cancer, microRNA-182 (miR-182) specifically targets BRCA1.^[58]
Almost all types of breast cancer were found to have an average of about 100-fold increase in miR-182, compared to normal breast tissue.^[59]
In breast cancer cell lines, there is an inverse correlation of BRCA1 protein levels with miR-182 expression.^[58]
Thus it appears that much of the reduction or absence of BRCA1 in high grade ductal breast cancers may be due to over-expressed miR-182.

In addition to miR-182, a pair of almost identical microRNAs, miR-146a and miR-146b-5p, also repress BRCA1 expression.
These two microRNAs are over-expressed in triple-negative tumors and their over-expression results in BRCA1 inactivation.^[60]
Thus, miR-146a and/or miR-146b-5p may also contribute to reduced expression of BRCA1 in these triple-negative breast cancers.

MicroRNA repression of BRCA1 in ovarian cancers

In both serous tubal intraepithelial carcinoma (the precursor lesion to high grade serous ovarian carcinoma (HG-SOC)), and in HG-SOC itself, miR-182 is overexpressed in about 70% of cases.^[61]
In cells with over-expressed miR-182, BRCA1 remained low, even after exposure to ionizing radiation (which normally raises BRCA1 expression).^[61]
Thus much of the reduced or absent BRCA1 in HG-SOC may be due to over-expressed miR-182.

Another microRNA known to reduce expression of BRCA1 in ovarian cancer cells is miR-9.^[52] Among 58 tumors from patients with stage IIIC or stage IV serous ovarian cancers (HG-SOG), an inverse correlation was found between expressions of miR-9 and BRCA1,^[52] so that increased miR-9 may also contribute to reduced expression of BRCA1 in these ovarian cancers.

Population or subgroup	BRCA1 mutation(s)^[62]	Reference(s)
African-Americans	943ins10, M1775R	^[63]
Afrikaners	E881X	^[64]
Ashkenazi Jewish	185delAG, 188del11, 5382insC	^[65]^[66]
Austrians	2795delA, C61G, 5382insC, Q1806stop	^[67]
Belgians	2804delAA, IVS5+3A>G	^[68]^[69]
Dutch	Exon 2 deletion, exon 13 deletion, 2804delAA	^[68]^[70]^[71]
Finns	3745delT, IVS11-2A>G	^[72]^[73]
French	3600del11, G1710X	^[74]
French Canadians	C4446T	^[75]
Germans	5382insC, 4184del4	^[76]^[77]
Greeks	5382insC	^[78]
Hungarians	300T>G, 5382insC, 185delAG	^[79]
Italians	5083del19	^[80]
Japanese	L63X, Q934X	^[81]
Native North Americans	1510insG, 1506A>G	^[82]
Northern Irish	2800delAA	^[83]
Norwegians	816delGT, 1135insA, 1675delA, 3347delAG	^[84]^[85]
Pakistanis	2080insA, 3889delAG, 4184del4, 4284delAG, IVS14-1A>G	^[86]
Polish	300T>G, 5382insC, C61G, 4153delA	^[87]^[88]
Russians	5382insC, 4153delA	^[89]
Scottish	2800delAA	^[83]^[90]
Spanish	R71G	^[91]^[92]
Swedish	Q563X, 3171ins5, 1201del11, 2594delC	^[63]^[93]

BRCA2

BRCA2 and BRCA1 are normally expressed in the cells of breast and other tissue, where they help repair damaged DNA or destroy cells if DNA cannot be repaired.
They are involved in the repair of chromosomal damage with an important role in the error-free repair of DNA double strand breaks.^[94]^[95]
If BRCA1 or BRCA2 itself is damaged by a BRCA mutation, damaged DNA is not repaired properly, and this increases the risk for breast cancer.^[96]^[47]
BRCA1 and BRCA2 have been described as "breast cancer susceptibility genes" and "breast cancer susceptibility proteins".
The predominant allele has a normal tumor suppressive function whereas high penetrance mutations in these genes cause a loss of tumor suppressive function, which correlates with an increased risk of breast cancer.^[97]

The BRCA2 gene is located on the long (q) arm of chromosome 13 at position 12.3 (13q12.3).^[98] The human reference BRCA 2 gene contains 27 exons, and the cDNA has 10,254 base pairs^[99] coding for a protein of 3418 amino acids.^[100]^[101]

Certain variations of the BRCA2 gene increase risks for breast cancer as part of a hereditary breast-ovarian cancer syndrome.
Researchers have identified hundreds of mutations in the BRCA2 gene, many of which cause an increased risk of cancer. BRCA2 mutations are usually insertions or deletions of a small number of DNA base pairs in the gene.
As a result of these mutations, the protein product of the BRCA2 gene is abnormal, and does not function properly. Researchers believe that the defective BRCA2 protein is unable to fix DNA damage that occurs throughout the genome.
As a result, there is an increase in mutations due to error-prone translesion synthesis past un-repaired DNA damage, and some of these mutations can cause cells to divide in an uncontrolled way and form a tumor.

In general, strongly inherited gene mutations (including mutations in BRCA2) account for only 5-10% of breast cancer cases; the specific risk of getting breast or other cancer for anyone carrying a BRCA2 mutation depends on many factors.^[102]

All germline BRCA2 mutations identified to date have been inherited, suggesting the possibility of a large "founder" effect in which a certain mutation is common to a well-defined population group and can theoretically be traced back to a common ancestor.
Given the complexity of mutation screening for BRCA2, these common mutations may simplify the methods required for mutation screening in certain populations
. Analysis of mutations that occur with high frequency also permits the study of their clinical expression.^[103] A
striking example of a founder mutation is found in Iceland, where a single BRCA2 (999del5) mutation accounts for virtually all breast/ovarian cancer families.^[104]^[105]
This frame-shift mutation leads to a highly truncated protein product. In a large study examining hundreds of cancer and control individuals, this 999del5 mutation was found in 0.6% of the general population
. Of note, while 72% of patients who were found to be carriers had a moderate or strong family history of breast cancer, 28% had little or no family history of the disease.
This strongly suggests the presence of modifying genes that affect the phenotypic expression of this mutation, or possibly the interaction of the BRCA2 mutation with environmental factors. Additional examples of founder mutations in BRCA2 are given in the table below.

Population or subgroup	BRCA2 mutation(s)^[103]^[62]	Reference(s)
Ashkenazi Jewish	6174delT	^[106]
Dutch	5579insA	^[71]
Finns	8555T>G, 999del5, IVS23-2A>G	^[72]^[73]
French Canadians	8765delAG, 3398delAAAAG	^[75]^[107]^[108]
Hungarians	9326insA	^[79]
Icelanders	999del5	^[104]^[105]
Italians	8765delAG	^[109]
Northern Irish	6503delTT	^[83]
Pakistanis	3337C>T	^[86]
Scottish	6503delTT	^[83]
Slovenians	IVS16-2A>G	^[110]
Spanish	3034delAAAC(codon936), 9254del5	^[111]
Swedish	4486delG	^[63]

Commercial BRCA mutation tests

The sensitivity of commercial BRCA mutation tests like 23andMe is debated.
For example, 23andMe’s testing formula is based on solely three genetic variants, most prevalent among Ashkenazi Jews, while most people carry other mutations of the gene.
This will result in false negative results.
23andMe is a commercial BRCA1 screening test, with more than 10 million customers.
Even if only a small percentage take the test, that’s thousands who could be misled.
As accurately stated by Prof. Mary-Claire King, who discovered the BRCA1, “The F.D.A. should not have permitted this out-of-date approach to be used for medical purposes. Misleading, falsely reassuring results from their incomplete testing can cost women’s lives.”

Blood chemistry

Blood chemistry tests measure certain chemicals in the blood. They show how well certain organs are functioning and can also be used to detect abnormalities. They are used to stage breast cancer. ^[112]

Urea (blood urea nitrogen or BUN) and creatinine may be measured to check kidney function. Kidney function is checked before chemotherapy is given and may be rechecked during or after treatment.
Alanine aminotransferase (ALT), aspartate transaminase (AST) and alkaline phosphatase may be measured to check liver function.

Increased levels could indicate that cancer has spread to the liver.

Alkaline phosphatase can also be used to check for cancer in the bone.

Increased levels could indicate that cancer has spread to the bone.
Tumor markers such as Ki67

References

↑ ^1.0 ^1.1 Mitri Z, Constantine T, O'Regan R (2012). "The HER2 Receptor in Breast Cancer: Pathophysiology, Clinical Use, and New Advances in Therapy". Chemotherapy Research and Practice. 2012: 743193. doi:10.1155/2012/743193. PMC 3539433. PMID 23320171.
↑ "ERBB2 erb-b2 receptor tyrosine kinase 2 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2016-06-14.
↑ Reference, Genetics Home. "ERBB2". Genetics Home Reference. Retrieved 2016-06-19.
↑ Barh D, Gunduz M (2015-01-22). Noninvasive Molecular Markers in Gynecologic Cancers. CRC Press. p. 427. ISBN 9781466569393.
↑ Roy V, Perez EA (November 2009). "Beyond trastuzumab: small molecule tyrosine kinase inhibitors in HER-2-positive breast cancer". The Oncologist. 14 (11): 1061–9. doi:10.1634/theoncologist.2009-0142. PMID 19887469.
↑ Telli ML, Hunt SA, Carlson RW, Guardino AE (August 2007). "Trastuzumab-related cardiotoxicity: calling into question the concept of reversibility". Journal of Clinical Oncology. 25 (23): 3525–33. doi:10.1200/JCO.2007.11.0106. PMID 17687157.
↑ Giuliano AE, Hurvitz SA (2019). "Breast Disorder". In Papadakis MA, McPhee SJ, Rabow MW. Current Medical Diagnosis & Treatment. New York, NY: McGraw-Hill.
↑ Ali SM, Carney WP, Esteva FJ, Fornier M, Harris L, Köstler WJ, Lotz JP, Luftner D, Pichon MF, Lipton A (September 2008). "Serum HER-2/neu and relative resistance to trastuzumab-based therapy in patients with metastatic breast cancer". Cancer. 113 (6): 1294–301. doi:10.1002/cncr.23689. PMID 18661530.
↑ Lennon S, Barton C, Banken L, Gianni L, Marty M, Baselga J, Leyland-Jones B (April 2009). "Utility of serum HER2 extracellular domain assessment in clinical decision making: pooled analysis of four trials of trastuzumab in metastatic breast cancer". Journal of Clinical Oncology. 27 (10): 1685–93. doi:10.1200/JCO.2008.16.8351. PMID 19255335.
↑ Burstein HJ (October 2005). "The distinctive nature of HER2-positive breast cancers". The New England Journal of Medicine. 353 (16): 1652–4. doi:10.1056/NEJMp058197. PMID 16236735.
↑ Tan M, Yu D (2007). "Molecular mechanisms of erbB2-mediated breast cancer chemoresistance". Advances in Experimental Medicine and Biology. Advances in Experimental Medicine and Biology. 608: 119–29. doi:10.1007/978-0-387-74039-3_9. ISBN 978-0-387-74037-9. PMID 17993237.
↑ Nagy P, Jenei A, Kirsch AK, Szöllosi J, Damjanovich S, Jovin TM (June 1999). "Activation-dependent clustering of the erbB2 receptor tyrosine kinase detected by scanning near-field optical microscopy". Journal of Cell Science. 112 (11): 1733–41. PMID 10318765.
↑ Kaufmann R, Müller P, Hildenbrand G, Hausmann M, Cremer C (April 2011). "Analysis of Her2/neu membrane protein clusters in different types of breast cancer cells using localization microscopy". Journal of Microscopy. 242 (1): 46–54. doi:10.1111/j.1365-2818.2010.03436.x. PMID 21118230.
↑ Yonesaka K, Zejnullahu K, Okamoto I, Satoh T, Cappuzzo F, Souglakos J, et al. (September 2011). "Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab". Science Translational Medicine. 3 (99): 99ra86. doi:10.1126/scitranslmed.3002442. PMC 3268675. PMID 21900593.
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@@ Line 1: / Line 1: @@
 __NOTOC__
-{{CMG}} {{AE}}{{Soroush}}
+{{CMG}} {{AE}}{{Soroush}}, Ammu Susheela, and Mirdula Sharma
 {{Breast cancer}}
 ==Overview==
-Laboratory studies play a crucial role in prevention, diagnosis, staging, treatment planning, management, determining prognosis and follow up of patients with breast cancer. Among them are single gene studies (i. e. BRCA1and 2, HER2), multiple gene panels (i.e. Oncotype DX),  tumor markers (Ki67), and metastatic markers such as serum [[alkaline phosphatase]] as a marker of bone metastasis. A variety of other blood chemistry tests are also used in the management process of patients with breast cancer, among them are liver function tests ([[Alanine transaminase|alanine aminotransferase]] ([[Alanine transaminase|ALT]]), [[aspartate transaminase]] ([[Aspartate transaminase|AST]]) , bilirubin, [[alkaline phosphatase]]) and markers of kidney function (BUN, creatinine).
+Laboratory studies play a crucial role in [[Prevention (medical)|prevention]], [[diagnosis]], [[Cancer staging|staging]], [[Treatment Planning|treatment planning]], management, determining [[prognosis]] and follow up of patients with breast cancer. Among them are single gene studies (i. e. [[BRCA1]], [[BRCA2]], and [[HER2]]), multiple gene panels (i.e. Oncotype DX),  [[Tumor marker|tumor markers]] (Ki67), and metastatic markers such as serum [[alkaline phosphatase]] as a marker of [[bone metastasis]]. A variety of other blood chemistry tests are also used in the management process of patients with breast cancer, among them are [[liver function tests]] ([[Alanine transaminase|alanine aminotransferase]] ([[Alanine transaminase|ALT]]), [[aspartate transaminase]] ([[Aspartate transaminase|AST]]) , [[bilirubin]], [[alkaline phosphatase]]) and markers of kidney function ([[Blood urea nitrogen|BUN]], [[creatinine]]).
+==HER2==
+*HER2 is a member of the human [[epidermal growth factor receptor]] (HER/EGFR/ERBB) family.
+*[[Gene duplication|Amplification]] or over-expression of this [[oncogene]] has been shown to play an important role in the development and progression of certain aggressive types of [[breast cancer]].
+*In recent years the protein has become an important [[Biomarker (medicine)|biomarker]] and target of therapy for approximately 30% of [[breast cancer]] patients.<ref name="pmid23320171" /> HER2 has several names among them are:
+:*'''Receptor tyrosine-protein kinase erbB-2'''
+:* '''CD340''' ([[cluster of differentiation]] 340)
+:* '''proto-oncogene Neu'''
+:* '''Erbb2''' (rodent), or '''ERBB2''' (human)
+:* '''''HER2''''' (from '''human epidermal growth factor receptor 2''')
+:* '''''HER2/neu''''' <ref>{{Cite web|url=https://www.ncbi.nlm.nih.gov/gene/2064|title=ERBB2 erb-b2 receptor tyrosine kinase 2 [Homo sapiens (human)] - Gene - NCBI|website=www.ncbi.nlm.nih.gov|access-date=2016-06-14}}</ref><ref>{{Cite web|url=https://ghr.nlm.nih.gov/gene/ERBB2|title=ERBB2|last=Reference|first=Genetics Home|website=Genetics Home Reference|access-date=2016-06-19}}</ref><ref>{{Cite book|url=https://books.google.com/books?id=xZoXBgAAQBAJ|title=Noninvasive Molecular Markers in Gynecologic Cancers|last=Barh|first=Debmalya|last2=Gunduz|first2=Mehmet | name-list-format = vanc |date=2015-01-22|publisher=CRC Press|page=427|isbn=9781466569393 }}</ref>
+===Signaling pathways===
+*Signaling pathways activated by HER2 include:<ref name="pmid19887469">{{cite journal | vauthors = Roy V, Perez EA | title = Beyond trastuzumab: small molecule tyrosine kinase inhibitors in HER-2-positive breast cancer | journal = The Oncologist | volume = 14 | issue = 11 | pages = 1061–9 | date = November 2009 | pmid = 19887469 | doi = 10.1634/theoncologist.2009-0142 }}</ref>
+:* [[mitogen-activated protein kinase]] (MAPK)
+:* [[phosphoinositide 3-kinase]] (PI3K/Akt)
+:* [[phospholipase C]] γ
+:* [[protein kinase C]] (PKC)
+:* [[STAT protein|Signal transducer and activator of transcription]] (STAT)
+*In a nutshell, signaling through the ErbB family of receptors promotes cell proliferation and opposes [[apoptosis]], and therefore must be tightly regulated to prevent uncontrolled cell growth from occurring.
+=== Cancer biopsy ===
+*HER2 testing is performed in breast cancer patients to assess prognosis and to determine suitability for trastuzumab therapy.
+*Trastuzumab has been associated with cardiac toxicity.<ref name="pmid17687157">{{cite journal | vauthors = Telli ML, Hunt SA, Carlson RW, Guardino AE | title = Trastuzumab-related cardiotoxicity: calling into question the concept of reversibility | journal = Journal of Clinical Oncology | volume = 25 | issue = 23 | pages = 3525–33 | date = August 2007 | pmid = 17687157 | doi = 10.1200/JCO.2007.11.0106 }}</ref>
+*Tests are usually performed on [[biopsy]] samples obtained by either [[fine-needle aspiration]],  core needle biopsy, [[vacuum-assisted breast biopsy]], or surgical excision.
+*[[Immunohistochemistry]] is used to measure the amount of HER2 protein present in the sample.
+*Examples of this assay include HercepTest, Dako, Glostrup, and Denmark. T
+*he sample is given a score based on the cell membrane staining pattern. Specimens with equivocal IHC results should then be validated using [[fluorescence in situ hybridisation]] (FISH).
+*FISH can be used to measure the number of copies of the gene which are present and is thought to be more reliable than IHC.<ref>{{cite book | vauthors = Giuliano AE, Hurvitz SA | chapter = Breast Disorder | veditors = Papadakis MA, McPhee SJ, Rabow MW | title = Current Medical Diagnosis & Treatment | year = 2019 | location = New York, NY | publisher = McGraw-Hill }}</ref>
+[[Image:3D Dual Color Super Resolution Microscopy Cremer 2010 .png|thumb|1000px|center|'''3D reconstruction of dual color acquistion of Her2/neu and Her 3.''' A) conventional wide-field fluorescence image of an AG11132 mammary epithelial cells. Her3 is labelled with Alexa488 (green) and Her2/neu with Alexa568 (red). B) magnified image of a small area of A. C) localization microscopy SPDM of the same region of interest as in B. D) and E) show a 3D reconstruction of the protein clusters using the combination of SPDM and SMI microscopy (LIMON technology). Scale bars in D) and E) are 500 nm in each direction. Source:<nowiki>https://commons.wikimedia.org/wiki/File:3D_Dual_Color_Super_Resolution_Microscopy_Cremer_2010.png</nowiki>]]
+=== Serum ===
+*The extracellular domain of HER2 can be shed from the surface of tumour cells and enter the circulation.
+*Measurement of serum HER2 by enzyme-linked immunosorbent assay ([[ELISA]]) offers a far less invasive method of determining HER2 status than a biopsy and consequently has been extensively investigated.
+*Results so far have suggested that changes in serum HER2 concentrations may be useful in predicting response to trastuzumab therapy.<ref name="pmid18661530">{{cite journal | vauthors = Ali SM, Carney WP, Esteva FJ, Fornier M, Harris L, Köstler WJ, Lotz JP, Luftner D, Pichon MF, Lipton A | title = Serum HER-2/neu and relative resistance to trastuzumab-based therapy in patients with metastatic breast cancer | journal = Cancer | volume = 113 | issue = 6 | pages = 1294–301 | date = September 2008 | pmid = 18661530 | doi = 10.1002/cncr.23689 }}</ref>
+*However, its ability to determine eligibility for trastuzumab therapy is less clear.<ref name="pmid19255335">{{cite journal | vauthors = Lennon S, Barton C, Banken L, Gianni L, Marty M, Baselga J, Leyland-Jones B | title = Utility of serum HER2 extracellular domain assessment in clinical decision making: pooled analysis of four trials of trastuzumab in metastatic breast cancer | journal = Journal of Clinical Oncology | volume = 27 | issue = 10 | pages = 1685–93 | date = April 2009 | pmid = 19255335 | doi = 10.1200/JCO.2008.16.8351 }}</ref>
+=== Cancer ===
+*Amplification, also known as the over-expression of the ''ERBB2'' gene, occurs in approximately 15-30% of [[breast cancer]]s.<ref name="pmid23320171">{{cite journal | vauthors = Mitri Z, Constantine T, O'Regan R | title = The HER2 Receptor in Breast Cancer: Pathophysiology, Clinical Use, and New Advances in Therapy | journal = Chemotherapy Research and Practice | volume = 2012 | issue =  | pages = 743193 | year = 2012 | pmid = 23320171 | pmc = 3539433 | doi = 10.1155/2012/743193 }}</ref><ref name="pmid16236735">{{cite journal | vauthors = Burstein HJ | title = The distinctive nature of HER2-positive breast cancers | journal = The New England Journal of Medicine | volume = 353 | issue = 16 | pages = 1652–4 | date = October 2005 | pmid = 16236735 | doi = 10.1056/NEJMp058197 }}</ref>
+*It is strongly associated with increased disease recurrence and a poor prognosis.<ref name="pmid17993237">{{cite journal | vauthors = Tan M, Yu D | title = Molecular mechanisms of erbB2-mediated breast cancer chemoresistance | journal = Advances in Experimental Medicine and Biology | volume = 608 | issue =  | pages = 119–29 | year = 2007 | pmid = 17993237 | doi = 10.1007/978-0-387-74039-3_9 | isbn = 978-0-387-74037-9 | series = Advances in Experimental Medicine and Biology }}</ref>
+*HER2 is colocalised and most of the time, coamplified with the gene [[GRB7]], which is a proto-oncogene associated with breast, testicular germ cell, gastric, and eosophageal tumours.
+*HER2 proteins have been shown to form clusters in cell membranes that may play a role in tumorigenesis.<ref name="pmid10318765">{{cite journal | vauthors = Nagy P, Jenei A, Kirsch AK, Szöllosi J, Damjanovich S, Jovin TM | title = Activation-dependent clustering of the erbB2 receptor tyrosine kinase detected by scanning near-field optical microscopy | journal = Journal of Cell Science | volume = 112 | issue = 11 | pages = 1733–41 | date = June 1999 | pmid = 10318765 | doi =  }}</ref><ref name="pmid21118230">{{cite journal | vauthors = Kaufmann R, Müller P, Hildenbrand G, Hausmann M, Cremer C | title = Analysis of Her2/neu membrane protein clusters in different types of breast cancer cells using localization microscopy | journal = Journal of Microscopy | volume = 242 | issue = 1 | pages = 46–54 | date = April 2011 | pmid = 21118230 | doi = 10.1111/j.1365-2818.2010.03436.x }}</ref>
+*Recent evidence has implicated HER2 signaling in resistance to the [[Epidermal growth factor receptor|EGFR]]-targeted cancer drug [[cetuximab]].<ref name="YonesakaZejnullahu2011">{{cite journal | vauthors = Yonesaka K, Zejnullahu K, Okamoto I, Satoh T, Cappuzzo F, Souglakos J, Ercan D, Rogers A, Roncalli M, Takeda M, Fujisaka Y, Philips J, Shimizu T, Maenishi O, Cho Y, Sun J, Destro A, Taira K, Takeda K, Okabe T, Swanson J, Itoh H, Takada M, Lifshits E, Okuno K, Engelman JA, Shivdasani RA, Nishio K, Fukuoka M, Varella-Garcia M, Nakagawa K, Jänne PA | display-authors = 6 | title = Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab | journal = Science Translational Medicine | volume = 3 | issue = 99 | pages = 99ra86 | date = September 2011 | pmid = 21900593 | pmc = 3268675 | doi = 10.1126/scitranslmed.3002442 }}</ref>
+=== Mutations ===
+*Furthermore, diverse structural alterations have been identified that cause ligand-independent firing of this receptor, doing so in the absence of receptor over-expression.
+*HER2 is found in a variety of tumours and some of these tumors carry point mutations in the sequence specifying the transmembrane domain of HER2.
+*Substitution of a valine for a glutamic acid in the transmembrane domain can result in the constitutive dimerization of this protein in the absence of a ligand.<ref>{{cite journal | vauthors = Brandt-Rauf PW, Rackovsky S, Pincus MR | title = Correlation of the structure of the transmembrane domain of the neu oncogene-encoded p185 protein with its function | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 87 | issue = 21 | pages = 8660–4 | date = November 1990 | pmid = 1978329 | pmc = 55017 | doi = 10.1073/pnas.87.21.8660 | bibcode = 1990PNAS...87.8660B }}</ref>
+*HER2 mutations have been found in [[non-small-cell lung cancer]]s (NSCLC) and can direct treatment.<ref name="Mazières2013">{{cite journal | vauthors = Mazières J, Peters S, Lepage B, Cortot AB, Barlesi F, Beau-Faller M, Besse B, Blons H, Mansuet-Lupo A, Urban T, Moro-Sibilot D, Dansin E, Chouaid C, Wislez M, Diebold J, Felip E, Rouquette I, Milia JD, Gautschi O | display-authors = 6 | title = Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives | journal = Journal of Clinical Oncology | volume = 31 | issue = 16 | pages = 1997–2003 | date = June 2013 | pmid = 23610105 | doi = 10.1200/JCO.2012.45.6095 }}</ref>
+=== As a drug target ===
+*HER2 is the target of the [[monoclonal antibodies|monoclonal antibody]] [[trastuzumab]] (marketed as Herceptin).
+*Trastuzumab is effective only in cancers where HER2 is over-expressed.
+*One year of trastuzumab therapy is recommended for all patients with HER2-positive breast cancer who are also receiving chemotherapy.<ref name="pmid25848335">{{cite journal | vauthors = Mates M, Fletcher GG, Freedman OC, Eisen A, Gandhi S, Trudeau ME, Dent SF | title = Systemic targeted therapy for her2-positive early female breast cancer: a systematic review of the evidence for the 2014 Cancer Care Ontario systemic therapy guideline | journal = Current Oncology | volume = 22 | issue = Suppl 1 | pages = S114-22 | date = March 2015 | pmid = 25848335 | pmc = 4381787 | doi = 10.3747/co.22.2322 }}</ref> Twelve months of trastuzumab therapy is optimal. Randomized trials have demonstrated no additional benefit beyond 12 months, whereas 6 months has been shown to be inferior to 12.
+*Trastuzumab is administered intravenously weekly or every 3 weeks.<ref>{{Cite book|title=Harrison's Principles of Internal Medicine, 20th ed.|last=Jameson et al.|first=|publisher=McGraw-Hill Education|year=2018|isbn=978-1-259-64403-0|location=|pages=Chapter 75: Breast Cancer}}</ref>
+*An important downstream effect of trastuzumab binding to HER2 is an increase in [[CDKN1B|p27]], a protein that halts cell proliferation.<ref name="Le_2005">{{cite journal | vauthors = Le XF, Pruefer F, Bast RC | title = HER2-targeting antibodies modulate the cyclin-dependent kinase inhibitor p27Kip1 via multiple signaling pathways | journal = Cell Cycle | volume = 4 | issue = 1 | pages = 87–95 | date = January 2005 | pmid = 15611642 | doi = 10.4161/cc.4.1.1360 }}</ref>
+*Another monoclonal antibody, [[Pertuzumab]], which inhibits dimerisation of HER2 and HER3 receptors, was approved by the FDA for use in combination with trastuzumab in June 2012.
+*As of November 2015, there are a number of ongoing and recently completed clinical trials of novel targeted agents for HER2+ metastatic breast cancer, e.g. [[margetuximab]].<ref>{{cite journal | vauthors = Jiang H, Rugo HS | title = Human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer: how the latest results are improving therapeutic options | journal = Therapeutic Advances in Medical Oncology | volume = 7 | issue = 6 | pages = 321–39 | date = November 2015 | pmid = 26557900 | pmc = 4622301 | doi = 10.1177/1758834015599389 }}</ref>
+*Additionally, [[NeuVax]] ([[Galena Biopharma]]) is a peptide-based immunotherapy that directs "killer" [[T cell]]s to target and destroy cancer cells that express HER2. It has entered phase 3 clinical trials.
+*It has been found that patients with ER+ ([[Estrogen receptor]] positive)/HER2+ compared with ER-/HER2+ breast cancers may actually benefit more from drugs that inhibit the [[PI3K/AKT/mTOR pathway|PI3K/AKT]] molecular pathway.<ref name="pmid19552798">{{cite journal | vauthors = Loi S, Sotiriou C, Haibe-Kains B, Lallemand F, Conus NM, Piccart MJ, Speed TP, McArthur GA | title = Gene expression profiling identifies activated growth factor signaling in poor prognosis (Luminal-B) estrogen receptor positive breast cancer | journal = BMC Medical Genomics | volume = 2 | issue =  | pages = 37 | year = 2009 | pmid = 19552798 | pmc = 2706265 | doi = 10.1186/1755-8794-2-37 | laysummary = https://www.sciencedaily.com/releases/2010/05/100506112557.htm | laysource = ScienceDaily }}</ref>
+*Over-expression of HER2 can also be suppressed by the amplification of other genes. Research is currently being conducted to discover which genes may have this desired effect.
+*The expression of HER2 is regulated by signaling through eostrogen receptors.
+*Normally, [[estradiol]] and [[tamoxifen]] acting through the eostrogen receptor down-regulate the expression of HER2.  However, when the ratio of the [[coactivator (genetics)|coactivator]] [[nuclear receptor coactivator 3|AIB-3]] exceeds that of the  [[corepressor (genetics)|corepressor]] [[PAX2]], the expression of HER2 is upregulated in the presence of tamoxifen, leading to tamoxifen-resistant [[breast cancer]].<ref name="urlCORDIS : News">{{cite web | url = http://cordis.europa.eu/fetch?CALLER=EN_NEWS&ACTION=D&SESSION=&RCN=30093 | title = Study sheds new light on tamoxifen resistance | authorlink = | date = 2008-11-13 | format = | work = Cordis News | publisher = Cordis | pages = | quote = | accessdate = 2008-11-14}}</ref><ref name="Hurtado1_2008">{{cite journal | vauthors = Hurtado A, Holmes KA, Geistlinger TR, Hutcheson IR, Nicholson RI, Brown M, Jiang J, Howat WJ, Ali S, Carroll JS | title = Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen | journal = Nature | volume = 456 | issue = 7222 | pages = 663–6 | date = December 2008 | pmid = 19005469 | pmc = 2920208 | doi = 10.1038/nature07483 | bibcode = 2008Natur.456..663H }}</ref>
+{{Clear}}
+==Multiple gene panels==
+*  '''Oncotype DX'''®''':'''
+:* For small hormone receptor-positive tumors that have not spread to more than 3 lymph nodes
+:* Also may be used for more advanced tumors
+:* Might be used for DCIS (ductal carcinoma in situ or stage 0 breast cancer). as well looks at a set of 21 genes in tumor biopsy samples to get a “recurrence score,” which is a number between 0 and 100.
+:* The score reflects the risk of breast cancer coming back (recurring) in the next 10 years and how likely you will benefit from getting chemo after surgery.
+:* '''The lower the score (usually 0-10) the lower the risk of recurrence'''.
+:* Benefit from chemotherapy is in doubt in most women with low scores
+:* '''An intermediate score (usually 11-25)''': '''intermediate risk of recurrence'''.
+:* Benefit from chemotherapy is in doubt in most women with intermediate-recurrence scores,
+:* Nevertheless chemotherapy is believed to be beneficial for women younger than 50 with a higher intermediate score (16-25)
+:* The possible risks and benefits of chemo should be weighted and discussed prior to decision making.
+:* '''A high score (usually 26-100): higher risk of recurrence'''.Chemotherapy is recommended for women with high scores in order to help lower the chance of cancer *recurrence.
+:* '''OncotypeDx is the only multigene panel with level I of evidence, and hence has been incorporated in the AJCC staging system'''
+*'''MammaPrint'''®''':'''
+:*To determine the likelihood of cancer recurrence in a distant part of the body after treatment.
+:*May be used in any type of breast cancer with stage 1 or 2 that has spread to no more than 3 lymph nodes.
+:*Hormone and HER2 status are also evaluated in this test.  Seventy different genes are examined in this test to determine the 10 years cancer recurrence
+:*The test results are reported as either “low risk” or “high risk.”
+:*'''Unlike OncotypeDx has not  been incorporated in the AJCC staging system''' '''yet.'''
 ==[[BRCA1]]/[[BRCA2]] ==
-Genetic markers, if present, suggest an increased likelihood of breast cancer occurrence.
 ===BRCA1===
-The human ''BRCA1'' gene is located on the long (q) arm of [[chromosome 17 (human)|chromosome 17]] at region 2 band 1, from [[base pair]] 41,196,312 to base pair 41,277,500 (Build GRCh37/hg19) [http://genome.ucsc.edu/cgi-bin/hgTracks?db=hg19&singleSearch=knownCanonical&position=BRCA1 (map)].<ref>National Center for Biotechnology Information, U.S. National Library of Medicine  [https://www.ncbi.nlm.nih.gov/gene/672 EntrezGene reference information for BRCA1 breast cancer 1, early onset (Homo sapiens)]</ref> ''BRCA1'' [[orthologs]] have been identified in most [[vertebrate]]s for which complete genome data are available <ref name="Ensembl">{{cite web |title=BRCA1 gene tree |url=http://www.ensembl.org/Multi/GeneTree/Image?gt=ENSGT00440000034289 |publisher=Ensembl}}</ref>.
+*The human ''BRCA1'' gene is located on the long (q) arm of [[chromosome 17 (human)|chromosome 17]] at region 2 band 1, from [[base pair]] 41,196,312 to base pair 41,277,500 (Build GRCh37/hg19) [http://genome.ucsc.edu/cgi-bin/hgTracks?db=hg19&singleSearch=knownCanonical&position=BRCA1 (map)].<ref>National Center for Biotechnology Information, U.S. National Library of Medicine  [https://www.ncbi.nlm.nih.gov/gene/672 EntrezGene reference information for BRCA1 breast cancer 1, early onset (Homo sapiens)]</ref>
+*''BRCA1'' [[orthologs]] have been identified in most [[vertebrate]]s for which complete genome data are available <ref name="Ensembl">{{cite web |title=BRCA1 gene tree |url=http://www.ensembl.org/Multi/GeneTree/Image?gt=ENSGT00440000034289 |publisher=Ensembl}}</ref>.
 ====Function and mechanism====
-BRCA1 is part of a complex that repairs [[double-strand breaks]] in DNA. The strands of the DNA double helix are continuously breaking as they become damaged. Sometimes only one strand is broken, sometimes both strands are broken simultaneously. DNA cross-linking agents are an important source of chromosome/DNA damage. Double-strand breaks occur as intermediates after the crosslinks are removed, and indeed, biallelic mutations in ''BRCA1'' have been identified to be responsible for [[Fanconi anemia|Fanconi Anemia]], Complementation Group S,<ref name="pmid25472942">{{cite journal |vauthors=Sawyer SL, Tian L, Kahkonen M, Schwartzentruber J, Kircher M, Majewski J, Dyment DA, Innes AM, Boycott KM, Moreau LA, Moilanen JS, Greenberg RA | title = Biallelic Mutations in BRCA1 Cause a New Fanconi Anemia Subtype | journal = Cancer Discov | volume = 5| issue = 2| pages = 135–42| year = 2014 | pmid = 25472942 | doi = 10.1158/2159-8290.CD-14-1156 | pmc=4320660}}</ref> a genetic disease associated with hypersensitivity to DNA crosslinking agents. BRCA1 is part of a protein complex that repairs DNA when both strands are broken. When this happens, it is difficult for the repair mechanism to "know" how to replace the correct DNA sequence, and there are multiple ways to attempt the repair. The double-strand repair mechanism in which BRCA1 participates is [[Homology directed repair|homology-directed repair]], where the repair proteins copy the identical sequence from the intact [[sister chromatid]].<ref>[http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/D/DNArepair.html#DSBs Kimball's Biologh Pages]</ref>
+*BRCA1 is part of a complex that '''repairs [[double-strand breaks]] in DNA'''. Th
+*In the nucleus of many types of normal cells, the BRCA1 protein interacts  with [[RAD51]] during repair of DNA double-strand breaks.<ref name="pmid17052168">{{cite journal | vauthors = Boulton SJ | title = Cellular functions of the BRCA tumour-suppressor proteins | journal = Biochem. Soc. Trans. | volume = 34 | issue = Pt 5 | pages = 633–45 | date = November 2006 | pmid = 17052168 | doi = 10.1042/BST0340633 }}</ref>
+*These breaks can be caused by natural radiation or other exposures, but also occur when [[chromosome]]s exchange genetic material (homologous recombination, e.g., "crossing over" during meiosis). TBy influencing DNA damage repair, these three proteins play a role in maintaining the stability of the human genome.
+*'''BRCA1 is also involved in another type of DNA repair, termed mismatch repair.'''
+*BRCA1 interacts with the DNA mismatch repair protein MSH2.<ref name="pmid11498787">{{cite journal | vauthors = Wang Q, Zhang H, Guerrette S, Chen J, Mazurek A, Wilson T, Slupianek A, Skorski T, Fishel R, Greene MI | title = Adenosine nucleotide modulates the physical interaction between hMSH2 and BRCA1 | journal = Oncogene | volume = 20 | issue = 34 | pages = 4640–9 | date = August 2001 | pmid = 11498787 | doi = 10.1038/sj.onc.1204625 }}</ref>
+*MSH2, MSH6, PARP and some other proteins involved in single-strand repair are reported to be elevated in BRCA1-deficient mammary tumors.<ref name="pmid22366898">{{cite journal | vauthors = Warmoes M, Jaspers JE, Pham TV, Piersma SR, Oudgenoeg G, Massink MP, Waisfisz Q, Rottenberg S, Boven E, Jonkers J, Jimenez CR | title = Proteomics of mouse BRCA1-deficient mammary tumors identifies DNA repair proteins with potential diagnostic and prognostic value in human breast cancer | journal = Mol. Cell. Proteomics | volume = 11 | issue = 7 | pages = M111.013334 | date = July 2012 | pmid = 22366898 | pmc = 3394939 | doi = 10.1074/mcp.M111.013334 }}</ref>
-In the nucleus of many types of normal cells, the BRCA1 protein interacts  with [[RAD51]] during repair of DNA double-strand breaks.<ref name="pmid17052168">{{cite journal | vauthors = Boulton SJ | title = Cellular functions of the BRCA tumour-suppressor proteins | journal = Biochem. Soc. Trans. | volume = 34 | issue = Pt 5 | pages = 633–45 | date = November 2006 | pmid = 17052168 | doi = 10.1042/BST0340633 }}</ref> These breaks can be caused by natural radiation or other exposures, but also occur when [[chromosome]]s exchange genetic material (homologous recombination, e.g., "crossing over" during meiosis). The [[BRCA2]] protein, which has a function similar to that of BRCA1, also interacts with the RAD51 protein. By influencing DNA damage repair, these three proteins play a role in maintaining the stability of the human genome.{{citation needed|date=January 2016}}
+*A protein called [[valosin-containing protein]] (VCP, also known as p97) plays a role to recruit BRCA1 to the damaged DNA sites.
+*
+*After ionizing radiation, VCP is recruited to DNA lesions and cooperates with the ubiquitin ligase RNF8 to orchestrate assembly of signaling complexes for efficient DSB repair.<ref name="pmid22020440">{{cite journal | vauthors = Meerang M, Ritz D, Paliwal S, Garajova Z, Bosshard M, Mailand N, Janscak P, Hübscher U, Meyer H, Ramadan K | title = The ubiquitin-selective segregase VCP/p97 orchestrates the response to DNA double-strand breaks | journal = Nat. Cell Biol. | volume = 13 | issue = 11 | pages = 1376–82 | date = November 2011 | pmid = 22020440 | doi = 10.1038/ncb2367 }}</ref>
+*BRCA1 interacts with VCP.<ref>{{cite journal | vauthors = Zhang H, Wang Q, Kajino K, Greene MI | title = VCP, a weak ATPase involved in multiple cellular events, interacts physically with BRCA1 in the nucleus of living cells | journal = DNA Cell Biol | volume = 19 | issue = 5 | pages = 253–263 | year = 2000 | pmid = 10855792 | doi = 10.1089/10445490050021168 }}</ref>
+*
+*BRCA1 also interacts with c-Myc, and other proteins that are critical to maintain genome stability.<ref name="pmid9788437">{{cite journal | vauthors = Wang Q, Zhang H, Kajino K, Greene MI | title = BRCA1 binds c-Myc and inhibits its transcriptional and transforming activity in cells | journal = Oncogene | volume = 17 | issue = 15 | pages = 1939–48 | date = October 1998 | pmid = 9788437 | doi = 10.1038/sj.onc.1202403 }}</ref>
-BRCA1 is also involved in another type of DNA repair, termed mismatch repair.  BRCA1 interacts with the DNA mismatch repair protein MSH2.<ref name="pmid11498787">{{cite journal | vauthors = Wang Q, Zhang H, Guerrette S, Chen J, Mazurek A, Wilson T, Slupianek A, Skorski T, Fishel R, Greene MI | title = Adenosine nucleotide modulates the physical interaction between hMSH2 and BRCA1 | journal = Oncogene | volume = 20 | issue = 34 | pages = 4640–9 | date = August 2001 | pmid = 11498787 | doi = 10.1038/sj.onc.1204625 }}</ref>  MSH2, MSH6, PARP and some other proteins involved in single-strand repair are reported to be elevated in BRCA1-deficient mammary tumors.<ref name="pmid22366898">{{cite journal | vauthors = Warmoes M, Jaspers JE, Pham TV, Piersma SR, Oudgenoeg G, Massink MP, Waisfisz Q, Rottenberg S, Boven E, Jonkers J, Jimenez CR | title = Proteomics of mouse BRCA1-deficient mammary tumors identifies DNA repair proteins with potential diagnostic and prognostic value in human breast cancer | journal = Mol. Cell. Proteomics | volume = 11 | issue = 7 | pages = M111.013334 | date = July 2012 | pmid = 22366898 | pmc = 3394939 | doi = 10.1074/mcp.M111.013334 }}</ref>
+*BRCA1 directly binds to DNA, with higher affinity for branched DNA structures. This ability to bind to DNA contributes to its ability to inhibit the nuclease activity of the [[Mre11-Rad50-Nbs1|MRN]] complex as well as the nuclease activity of Mre11 alone.<ref name="Paull2001">{{cite journal | vauthors = Paull TT, Cortez D, Bowers B, Elledge SJ, Gellert M | title = Direct DNA binding by Brca1 | journal = Proceedings of the National Academy of Sciences | volume = 98 | issue = 11 | pages = 6086–6091 | year = 2001 | pmid = 11353843 | pmc = 33426 | doi = 10.1073/pnas.111125998 }}</ref>
+*
+*This may explain a role for BRCA1 to promote lower fidelity DNA repair by [[non-homologous end joining]] (NHEJ).<ref name="Durant2005">{{cite journal | vauthors = Durant ST, Nickoloff JA | title = Good timing in the cell cycle for precise DNA repair by BRCA1 | journal = Cell Cycle | volume = 4 | issue = 9 | pages = 1216–22 | year = 2005 | pmid = 16103751 | doi = 10.4161/cc.4.9.2027 }}</ref>
+*BRCA1 also colocalizes with γ-H2AX (histone H2AX phosphorylated on serine-139) in DNA double-strand break repair foci, indicating it may play a role in recruiting repair factors.<ref name="Starita2003" /><ref name="Ye2001">{{cite journal | vauthors = Ye Q, Hu YF, Zhong H, Nye AC, Belmont AS, Li R | title = BRCA1-induced large-scale chromatin unfolding and allele-specific effects of cancer-predisposing mutations | journal = The Journal of Cell Biology | volume = 155 | issue = 6 | pages = 911–922 | year = 2001 | pmid = 11739404 | pmc = 2150890 | doi = 10.1083/jcb.200108049 }}</ref>
-A protein called [[valosin-containing protein]] (VCP, also known as p97) plays a role to recruit BRCA1 to the damaged DNA sites.  After ionizing radiation, VCP is recruited to DNA lesions and cooperates with the ubiquitin ligase RNF8 to orchestrate assembly of signaling complexes for efficient DSB repair.<ref name="pmid22020440">{{cite journal | vauthors = Meerang M, Ritz D, Paliwal S, Garajova Z, Bosshard M, Mailand N, Janscak P, Hübscher U, Meyer H, Ramadan K | title = The ubiquitin-selective segregase VCP/p97 orchestrates the response to DNA double-strand breaks | journal = Nat. Cell Biol. | volume = 13 | issue = 11 | pages = 1376–82 | date = November 2011 | pmid = 22020440 | doi = 10.1038/ncb2367 }}</ref>  BRCA1 interacts with VCP.<ref>{{cite journal | vauthors = Zhang H, Wang Q, Kajino K, Greene MI | title = VCP, a weak ATPase involved in multiple cellular events, interacts physically with BRCA1 in the nucleus of living cells | journal = DNA Cell Biol | volume = 19 | issue = 5 | pages = 253–263 | year = 2000 | pmid = 10855792 | doi = 10.1089/10445490050021168 }}</ref> BRCA1 also interacts with c-Myc, and other proteins that are critical to maintain genome stability.<ref name="pmid9788437">{{cite journal | vauthors = Wang Q, Zhang H, Kajino K, Greene MI | title = BRCA1 binds c-Myc and inhibits its transcriptional and transforming activity in cells | journal = Oncogene | volume = 17 | issue = 15 | pages = 1939–48 | date = October 1998 | pmid = 9788437 | doi = 10.1038/sj.onc.1202403 }}</ref>
+*[[Formaldehyde]] and [[acetaldehyde]] are common environmental sources of DNA cross links that often require repairs mediated by BRCA1 containing pathways.<ref name="Friedenson_2012">{{cite journal | vauthors = Friedenson B | title = A common environmental carcinogen unduly affects carriers of cancer mutations: carriers of genetic mutations in a specific protective response are more susceptible to an environmental carcinogen | journal = Med. Hypotheses | volume = 77 | issue = 5 | pages = 791–7 | date = November 2011 | pmid = 21839586 | doi = 10.1016/j.mehy.2011.07.039 }}</ref><ref name="Ridpath_2007">{{cite journal | vauthors = Ridpath JR, Nakamura A, Tano K, Luke AM, Sonoda E, Arakawa H, Buerstedde JM, Gillespie DA, Sale JE, Yamazoe M, Bishop DK, Takata M, Takeda S, Watanabe M, Swenberg JA, Nakamura J | title = Cells deficient in the FANC/BRCA pathway are hypersensitive to plasma levels of formaldehyde | journal = Cancer Res. | volume = 67 | issue = 23 | pages = 11117–22 | date = December 2007 | pmid = 18056434 | doi = 10.1158/0008-5472.CAN-07-3028 }}</ref>
-BRCA1 directly binds to DNA, with higher affinity for branched DNA structures. This ability to bind to DNA contributes to its ability to inhibit the nuclease activity of the [[Mre11-Rad50-Nbs1|MRN]] complex as well as the nuclease activity of Mre11 alone.<ref name="Paull2001">{{cite journal | vauthors = Paull TT, Cortez D, Bowers B, Elledge SJ, Gellert M | title = Direct DNA binding by Brca1 | journal = Proceedings of the National Academy of Sciences | volume = 98 | issue = 11 | pages = 6086–6091 | year = 2001 | pmid = 11353843 | pmc = 33426 | doi = 10.1073/pnas.111125998 }}</ref> This may explain a role for BRCA1 to promote lower fidelity DNA repair by [[non-homologous end joining]] (NHEJ).<ref name="Durant2005">{{cite journal | vauthors = Durant ST, Nickoloff JA | title = Good timing in the cell cycle for precise DNA repair by BRCA1 | journal = Cell Cycle | volume = 4 | issue = 9 | pages = 1216–22 | year = 2005 | pmid = 16103751 | doi = 10.4161/cc.4.9.2027 }}</ref> BRCA1 also colocalizes with γ-H2AX (histone H2AX phosphorylated on serine-139) in DNA double-strand break repair foci, indicating it may play a role in recruiting repair factors.<ref name="Starita2003" /><ref name="Ye2001">{{cite journal | vauthors = Ye Q, Hu YF, Zhong H, Nye AC, Belmont AS, Li R | title = BRCA1-induced large-scale chromatin unfolding and allele-specific effects of cancer-predisposing mutations | journal = The Journal of Cell Biology | volume = 155 | issue = 6 | pages = 911–922 | year = 2001 | pmid = 11739404 | pmc = 2150890 | doi = 10.1083/jcb.200108049 }}</ref>
+*This DNA repair function is essential; mice with loss-of-function mutations in both BRCA1 alleles are not viable, and as of 2015 only two adults were known to have loss-of-function mutations in both alleles; both had congenital or developmental issues, and both had cancer. One was presumed to have survived to adulthood because one of the BRCA1 mutations was [[hypomorphic]].<ref>{{cite journal | vauthors = Prakash R, Zhang Y, Feng W, Jasin M | title = Homologous recombination and human health: the roles of BRCA1, BRCA2, and associated proteins | journal = Cold Spring Harbor Perspectives in Biology | volume = 7 | issue = 4 | pages = a016600 | date = April 2015 | pmid = 25833843 | pmc = 4382744 | doi = 10.1101/cshperspect.a016600 }}</ref>
+*
-[[Formaldehyde]] and [[acetaldehyde]] are common environmental sources of DNA cross links that often require repairs mediated by BRCA1 containing pathways.<ref name="Friedenson_2012">{{cite journal | vauthors = Friedenson B | title = A common environmental carcinogen unduly affects carriers of cancer mutations: carriers of genetic mutations in a specific protective response are more susceptible to an environmental carcinogen | journal = Med. Hypotheses | volume = 77 | issue = 5 | pages = 791–7 | date = November 2011 | pmid = 21839586 | doi = 10.1016/j.mehy.2011.07.039 }}</ref><ref name="Ridpath_2007">{{cite journal | vauthors = Ridpath JR, Nakamura A, Tano K, Luke AM, Sonoda E, Arakawa H, Buerstedde JM, Gillespie DA, Sale JE, Yamazoe M, Bishop DK, Takata M, Takeda S, Watanabe M, Swenberg JA, Nakamura J | title = Cells deficient in the FANC/BRCA pathway are hypersensitive to plasma levels of formaldehyde | journal = Cancer Res. | volume = 67 | issue = 23 | pages = 11117–22 | date = December 2007 | pmid = 18056434 | doi = 10.1158/0008-5472.CAN-07-3028 }}</ref>
+*'''Certain variations of the ''BRCA1'' gene lead to an increased risk for [[breast cancer]] as part of a [[hereditary breast-ovarian cancer syndrome]]'''.
+*Researchers have identified hundreds of [[mutation]]s in the ''BRCA1'' gene, many of which are associated with an increased risk of cancer.
+*Females with an abnormal BRCA1 or BRCA2 gene have up to an 80% risk of developing breast cancer by age 90; increased risk of developing ovarian cancer is about 55% for females with BRCA1 mutations and about 25% for females with BRCA2 mutations.<ref name="urlGenetics">{{cite web | url = http://www.breastcancer.org/risk/factors/genetics | title = Genetics | date = 2012-09-17 | work = | publisher = Breastcancer.org | accessdate = }}</ref>
-This DNA repair function is essential; mice with loss-of-function mutations in both BRCA1 alleles are not viable, and as of 2015 only two adults were known to have loss-of-function mutations in both alleles; both had congenital or developmental issues, and both had cancer. One was presumed to have survived to adulthood because one of the BRCA1 mutations was [[hypomorphic]].<ref>{{cite journal | vauthors = Prakash R, Zhang Y, Feng W, Jasin M | title = Homologous recombination and human health: the roles of BRCA1, BRCA2, and associated proteins | journal = Cold Spring Harbor Perspectives in Biology | volume = 7 | issue = 4 | pages = a016600 | date = April 2015 | pmid = 25833843 | pmc = 4382744 | doi = 10.1101/cshperspect.a016600 }}</ref>
+*These mutations can be changes in one or a small number of DNA [[base pair]]s (the building-blocks of DNA), and can be identified with PCR and DNA sequencing.
-Certain variations of the ''BRCA1'' gene lead to an increased risk for [[breast cancer]] as part of a [[hereditary breast-ovarian cancer syndrome]]. Researchers have identified hundreds of [[mutation]]s in the ''BRCA1'' gene, many of which are associated with an increased risk of cancer. Females with an abnormal BRCA1 or BRCA2 gene have up to an 80% risk of developing breast cancer by age 90; increased risk of developing ovarian cancer is about 55% for females with BRCA1 mutations and about 25% for females with BRCA2 mutations.<ref name="urlGenetics">{{cite web | url = http://www.breastcancer.org/risk/factors/genetics | title = Genetics | date = 2012-09-17 | work = | publisher = Breastcancer.org | accessdate = }}</ref>
+*In some cases, large segments of DNA are rearranged. Those large segments, also called large rearrangements, can be a deletion or a duplication of one or several exons in the gene.
+*
+*Classical methods for mutation detection (sequencing) are unable to reveal these types of mutation.<ref name="pmid15832305">{{cite journal | vauthors = Mazoyer S | title = Genomic rearrangements in the BRCA1 and BRCA2 genes | journal = Hum. Mutat. | volume = 25 | issue = 5 | pages = 415–22 | date = May 2005 | pmid = 15832305 | doi = 10.1002/humu.20169 }}</ref>
+*Other methods have been proposed: traditional [[quantitative PCR]],<ref name="pmid14984472">{{cite journal | vauthors = Barrois M, Bièche I, Mazoyer S, Champème MH, Bressac-de Paillerets B, Lidereau R | title = Real-time PCR-based gene dosage assay for detecting BRCA1 rearrangements in breast-ovarian cancer families | journal = Clin. Genet. | volume = 65 | issue = 2 | pages = 131–6 | date = February 2004 | pmid = 14984472 | doi = 10.1111/j.0009-9163.2004.00200.x }}</ref> [[Multiplex Ligation-dependent Probe Amplification]] (MLPA),<ref name="pmid12670888">{{cite journal | vauthors = Hogervorst FB, Nederlof PM, Gille JJ, McElgunn CJ, Grippeling M, Pruntel R, Regnerus R, van Welsem T, van Spaendonk R, Menko FH, Kluijt I, Dommering C, Verhoef S, Schouten JP, van't Veer LJ, Pals G | title = Large genomic deletions and duplications in the BRCA1 gene identified by a novel quantitative method | journal = Cancer Res. | volume = 63 | issue = 7 | pages = 1449–53 | date = April 2003 | pmid = 12670888 | doi = }}</ref> and Quantitative Multiplex PCR of Short Fluorescent Fragments (QMPSF).<ref name="pmid12203994">{{cite journal | vauthors = Casilli F, Di Rocco ZC, Gad S, Tournier I, Stoppa-Lyonnet D, Frebourg T, Tosi M | title = Rapid detection of novel BRCA1 rearrangements in high-risk breast-ovarian cancer families using multiplex PCR of short fluorescent fragments | journal = Hum. Mutat. | volume = 20 | issue = 3 | pages = 218–26 | date = September 2002 | pmid = 12203994 | doi = 10.1002/humu.10108 }}</ref>
+*Newer methods have also been recently proposed: heteroduplex analysis (HDA) by multi-capillary electrophoresis or also dedicated oligonucleotides array based on [[comparative genomic hybridization]] (array-CGH).<ref name="pmid17718857">{{cite journal | vauthors = Rouleau E, Lefol C, Tozlu S, Andrieu C, Guy C, Copigny F, Nogues C, Bieche I, Lidereau R | title = High-resolution oligonucleotide array-CGH applied to the detection and characterization of large rearrangements in the hereditary breast cancer gene BRCA1 | journal = Clin. Genet. | volume = 72 | issue = 3 | pages = 199–207 | date = September 2007 | pmid = 17718857 | doi = 10.1111/j.1399-0004.2007.00849.x }}</ref>
+*
-These mutations can be changes in one or a small number of DNA [[base pair]]s (the building-blocks of DNA), and can be identified with PCR and DNA sequencing.{{citation needed|date=January 2016}}
+*Some results suggest that [[methylation|hypermethylation]] of the BRCA1 [[Promoter (biology)|promoter]], which has been reported in some cancers, could be considered as an inactivating mechanism for BRCA1 expression.<ref name="pmid18567944">{{cite journal | vauthors = Tapia T, Smalley SV, Kohen P, Muñoz A, Solis LM, Corvalan A, Faundez P, Devoto L, Camus M, Alvarez M, Carvallo P | title = Promoter hypermethylation of BRCA1 correlates with absence of expression in hereditary breast cancer tumors | journal = Epigenetics | volume = 3 | issue = 1 | pages = 157–63 | year = 2008 | pmid = 18567944 | doi = 10.1186/bcr1858 }}</ref>
-In some cases, large segments of DNA are rearranged. Those large segments, also called large rearrangements, can be a deletion or a duplication of one or several exons in the gene. Classical methods for mutation detection (sequencing) are unable to reveal these types of mutation.<ref name="pmid15832305">{{cite journal | vauthors = Mazoyer S | title = Genomic rearrangements in the BRCA1 and BRCA2 genes | journal = Hum. Mutat. | volume = 25 | issue = 5 | pages = 415–22 | date = May 2005 | pmid = 15832305 | doi = 10.1002/humu.20169 }}</ref> Other methods have been proposed: traditional [[quantitative PCR]],<ref name="pmid14984472">{{cite journal | vauthors = Barrois M, Bièche I, Mazoyer S, Champème MH, Bressac-de Paillerets B, Lidereau R | title = Real-time PCR-based gene dosage assay for detecting BRCA1 rearrangements in breast-ovarian cancer families | journal = Clin. Genet. | volume = 65 | issue = 2 | pages = 131–6 | date = February 2004 | pmid = 14984472 | doi = 10.1111/j.0009-9163.2004.00200.x }}</ref> [[Multiplex Ligation-dependent Probe Amplification]] (MLPA),<ref name="pmid12670888">{{cite journal | vauthors = Hogervorst FB, Nederlof PM, Gille JJ, McElgunn CJ, Grippeling M, Pruntel R, Regnerus R, van Welsem T, van Spaendonk R, Menko FH, Kluijt I, Dommering C, Verhoef S, Schouten JP, van't Veer LJ, Pals G | title = Large genomic deletions and duplications in the BRCA1 gene identified by a novel quantitative method | journal = Cancer Res. | volume = 63 | issue = 7 | pages = 1449–53 | date = April 2003 | pmid = 12670888 | doi = }}</ref> and Quantitative Multiplex PCR of Short Fluorescent Fragments (QMPSF).<ref name="pmid12203994">{{cite journal | vauthors = Casilli F, Di Rocco ZC, Gad S, Tournier I, Stoppa-Lyonnet D, Frebourg T, Tosi M | title = Rapid detection of novel BRCA1 rearrangements in high-risk breast-ovarian cancer families using multiplex PCR of short fluorescent fragments | journal = Hum. Mutat. | volume = 20 | issue = 3 | pages = 218–26 | date = September 2002 | pmid = 12203994 | doi = 10.1002/humu.10108 }}</ref> Newer methods have also been recently proposed: heteroduplex analysis (HDA) by multi-capillary electrophoresis or also dedicated oligonucleotides array based on [[comparative genomic hybridization]] (array-CGH).<ref name="pmid17718857">{{cite journal | vauthors = Rouleau E, Lefol C, Tozlu S, Andrieu C, Guy C, Copigny F, Nogues C, Bieche I, Lidereau R | title = High-resolution oligonucleotide array-CGH applied to the detection and characterization of large rearrangements in the hereditary breast cancer gene BRCA1 | journal = Clin. Genet. | volume = 72 | issue = 3 | pages = 199–207 | date = September 2007 | pmid = 17718857 | doi = 10.1111/j.1399-0004.2007.00849.x }}</ref>
+*A mutated ''BRCA1'' gene usually makes a [[protein]] that does not function properly
+*. Researchers believe that the defective BRCA1 protein is unable to help fix DNA damage leading to mutations in other genes.
+*These mutations can accumulate and may allow cells to grow and divide uncontrollably to form a tumor. Thus, BRCA1 inactivating mutations lead to a predisposition for cancer.
-Some results suggest that [[methylation|hypermethylation]] of the BRCA1 [[Promoter (biology)|promoter]], which has been reported in some cancers, could be considered as an inactivating mechanism for BRCA1 expression.<ref name="pmid18567944">{{cite journal | vauthors = Tapia T, Smalley SV, Kohen P, Muñoz A, Solis LM, Corvalan A, Faundez P, Devoto L, Camus M, Alvarez M, Carvallo P | title = Promoter hypermethylation of BRCA1 correlates with absence of expression in hereditary breast cancer tumors | journal = Epigenetics | volume = 3 | issue = 1 | pages = 157–63 | year = 2008 | pmid = 18567944 | doi = 10.1186/bcr1858 }}</ref>
+*BRCA1 mRNA [[three prime untranslated region|3' UTR]] can be bound by an [[miRNA]], [[Mir-17 microRNA precursor family|Mir-17 microRNA]]. It has been suggested that variations in this miRNA along with [[Mir-30 microRNA precursor|Mir-30 microRNA]] could confer susceptibility to breast cancer.<ref>{{cite journal | vauthors = Shen J, Ambrosone CB, Zhao H | title = Novel genetic variants in microRNA genes and familial breast cancer | journal = Int. J. Cancer | volume = 124 | issue = 5 | pages = 1178–82 | date = March 2009 | pmid = 19048628 | doi = 10.1002/ijc.24008 }}</ref>
-A mutated ''BRCA1'' gene usually makes a [[protein]] that does not function properly. Researchers believe that the defective BRCA1 protein is unable to help fix DNA damage leading to mutations in other genes. These mutations can accumulate and may allow cells to grow and divide uncontrollably to form a tumor. Thus, BRCA1 inactivating mutations lead to a predisposition for cancer.{{citation needed|date=January 2016}}
+*In addition to breast cancer, mutations in the ''BRCA1'' gene also increase the risk of [[ovarian cancer|ovarian]] and [[prostate cancer]]s. Moreover, precancerous lesions ([[dysplasia]]) within the [[Fallopian tube]] have been linked to ''BRCA1'' gene mutations. Pathogenic mutations anywhere in a model pathway containing BRCA1 and BRCA2 greatly increase risks for a subset of leukemias and lymphomas.<ref name="pmid17683622" />
-BRCA1 mRNA [[three prime untranslated region|3' UTR]] can be bound by an [[miRNA]], [[Mir-17 microRNA precursor family|Mir-17 microRNA]]. It has been suggested that variations in this miRNA along with [[Mir-30 microRNA precursor|Mir-30 microRNA]] could confer susceptibility to breast cancer.<ref>{{cite journal | vauthors = Shen J, Ambrosone CB, Zhao H | title = Novel genetic variants in microRNA genes and familial breast cancer | journal = Int. J. Cancer | volume = 124 | issue = 5 | pages = 1178–82 | date = March 2009 | pmid = 19048628 | doi = 10.1002/ijc.24008 }}</ref>
+*Females who have inherited a defective BRCA1 or BRCA2 gene are at a greatly elevated risk to develop breast and ovarian cancer.
+*Their risk of developing breast and/or ovarian cancer is so high, and so specific to those cancers, that many mutation carriers choose to have prophylactic surgery.
-In addition to breast cancer, mutations in the ''BRCA1'' gene also increase the risk of [[ovarian cancer|ovarian]] and [[prostate cancer]]s. Moreover, precancerous lesions ([[dysplasia]]) within the [[Fallopian tube]] have been linked to ''BRCA1'' gene mutations. Pathogenic mutations anywhere in a model pathway containing BRCA1 and BRCA2 greatly increase risks for a subset of leukemias and lymphomas.<ref name="pmid17683622" />
+*There has been much conjecture to explain such apparently striking tissue specificity.
+*Major determinants of where BRCA1/2 hereditary cancers occur are related to tissue specificity of the cancer pathogen, the agent that causes chronic inflammation or the carcinogen.
-Females who have inherited a defective BRCA1 or BRCA2 gene are at a greatly elevated risk to develop breast and ovarian cancer. Their risk of developing breast and/or ovarian cancer is so high, and so specific to those cancers, that many mutation carriers choose to have prophylactic surgery. There has been much conjecture to explain such apparently striking tissue specificity. Major determinants of where BRCA1/2 hereditary cancers occur are related to tissue specificity of the cancer pathogen, the agent that causes chronic inflammation or the carcinogen. The target tissue may have receptors for the pathogen, may become selectively exposed to an inflammatory process or to a carcinogen. An innate genomic deficit in a tumor suppressor gene impairs normal responses and exacerbates the susceptibility to disease in organ targets. This theory also fits data for several tumor suppressors beyond BRCA1 or BRCA2. A major advantage of this model is that it suggests there may be some options in addition to prophylactic surgery.<ref name="Levin2012">{{cite journal | vauthors = Levin B, Lech D, Friedenson B | title = Evidence that BRCA1- or BRCA2-associated cancers are not inevitable | journal = Mol Med | volume = 18 | issue = 9 | pages = 1327–37 | year = 2012 | pmid = 22972572 | pmc = 3521784 | doi = 10.2119/molmed.2012.00280 }}</ref>
+*The target tissue may have receptors for the pathogen, may become selectively exposed to an inflammatory process or to a carcinogen.
+*An innate genomic deficit in a tumor suppressor gene impairs normal responses and exacerbates the susceptibility to disease in organ targets.
+*This theory also fits data for several tumor suppressors beyond BRCA1 or BRCA2. A major advantage of this model is that it suggests there may be some options in addition to prophylactic surgery.<ref name="Levin2012">{{cite journal | vauthors = Levin B, Lech D, Friedenson B | title = Evidence that BRCA1- or BRCA2-associated cancers are not inevitable | journal = Mol Med | volume = 18 | issue = 9 | pages = 1327–37 | year = 2012 | pmid = 22972572 | pmc = 3521784 | doi = 10.2119/molmed.2012.00280 }}</ref>
 =====Low expression of ''BRCA1'' in breast and ovarian cancers=====
-BRCA1 expression is reduced or undetectable in the majority of high grade, ductal breast cancers.<ref name="pmid9988281">{{cite journal |vauthors=Wilson CA, Ramos L, Villaseñor MR, Anders KH, Press MF, Clarke K, Karlan B, Chen JJ, Scully R, Livingston D, Zuch RH, Kanter MH, Cohen S, Calzone FJ, Slamon DJ |title=Localization of human BRCA1 and its loss in high-grade, non-inherited breast carcinomas |journal=Nat. Genet. |volume=21 |issue=2 |pages=236–40 |year=1999 |pmid=9988281 |doi=10.1038/6029 |url=}}</ref>  It has long been noted that loss of BRCA1 activity, either by germ-line mutations or by down-regulation of gene expression, leads to tumor formation in specific target tissues.  In particular, decreased BRCA1 expression contributes to both sporadic and inherited breast tumor progression.<ref name="pmid12559046">{{cite journal |vauthors=Mueller CR, Roskelley CD |title=Regulation of BRCA1 expression and its relationship to sporadic breast cancer |journal=Breast Cancer Res. |volume=5 |issue=1 |pages=45–52 |year=2003 |pmid=12559046 |pmc=154136 |doi= 10.1186/bcr557}}</ref>  Reduced expression of BRCA1 is tumorigenic because it plays an important role in the repair of DNA damages, especially double-strand breaks, by the potentially error-free pathway of homologous recombination.<ref name="Jacinto">{{cite journal |vauthors=Jacinto FV, Esteller M |title=Mutator pathways unleashed by epigenetic silencing in human cancer |journal=Mutagenesis |volume=22 |issue=4 |pages=247–53 |year=2007 |pmid=17412712 |doi=10.1093/mutage/gem009 |url=}}</ref>  Since cells that lack the BRCA1 protein tend to repair DNA damages by alternative more error-prone mechanisms, the reduction or silencing of this protein generates mutations and gross chromosomal rearrangements that can lead to progression to breast cancer.<ref name="Jacinto" />
+*BRCA1 expression is reduced or undetectable in the majority of high grade, ductal breast cancers.<ref name="pmid9988281">{{cite journal |vauthors=Wilson CA, Ramos L, Villaseñor MR, Anders KH, Press MF, Clarke K, Karlan B, Chen JJ, Scully R, Livingston D, Zuch RH, Kanter MH, Cohen S, Calzone FJ, Slamon DJ |title=Localization of human BRCA1 and its loss in high-grade, non-inherited breast carcinomas |journal=Nat. Genet. |volume=21 |issue=2 |pages=236–40 |year=1999 |pmid=9988281 |doi=10.1038/6029 |url=}}</ref>
+*It has long been noted that loss of BRCA1 activity, either by germ-line mutations or by down-regulation of gene expression, leads to tumor formation in specific target tissues.
+*In particular, decreased BRCA1 expression contributes to both sporadic and inherited breast tumor progression.<ref name="pmid12559046">{{cite journal |vauthors=Mueller CR, Roskelley CD |title=Regulation of BRCA1 expression and its relationship to sporadic breast cancer |journal=Breast Cancer Res. |volume=5 |issue=1 |pages=45–52 |year=2003 |pmid=12559046 |pmc=154136 |doi= 10.1186/bcr557}}</ref>
+*Reduced expression of BRCA1 is tumorigenic because it plays an important role in the repair of DNA damages, especially double-strand breaks, by the potentially error-free pathway of homologous recombination.<ref name="Jacinto">{{cite journal |vauthors=Jacinto FV, Esteller M |title=Mutator pathways unleashed by epigenetic silencing in human cancer |journal=Mutagenesis |volume=22 |issue=4 |pages=247–53 |year=2007 |pmid=17412712 |doi=10.1093/mutage/gem009 |url=}}</ref>
+*Since cells that lack the BRCA1 protein tend to repair DNA damages by alternative more error-prone mechanisms, the reduction or silencing of this protein generates mutations and gross chromosomal rearrangements that can lead to progression to breast cancer.<ref name="Jacinto" />
-Similarly, BRCA1 expression is low in the majority (55%) of sporadic [[Ovarian cancer#Epithelial carcinoma|epithelial ovarian cancers (EOCs)]] where EOCs are the most common type of ovarian cancer, representing approximately 90% of ovarian cancers.<ref name="Sun">{{cite journal |vauthors=Sun C, Li N, Yang Z, Zhou B, He Y, Weng D, Fang Y, Wu P, Chen P, Yang X, Ma D, Zhou J, Chen G |title=miR-9 regulation of BRCA1 and ovarian cancer sensitivity to cisplatin and PARP inhibition |journal=J. Natl. Cancer Inst. |volume=105 |issue=22 |pages=1750–8 |year=2013 |pmid=24168967 |doi=10.1093/jnci/djt302 |url=}}</ref>  In [[Ovarian cancer#Serous carcinoma|serous ovarian carcinomas]], a sub-category constituting about 2/3 of EOCs, low BRCA1 expression occurs in more than 50% of cases.<ref name="pmid22790015">{{cite journal |vauthors=McMillen BD, Aponte MM, Liu Z, Helenowski IB, Scholtens DM, Buttin BM, Wei JJ |title=Expression analysis of MIR182 and its associated target genes in advanced ovarian carcinoma |journal=Mod. Pathol. |volume=25 |issue=12 |pages=1644–53 |year=2012 |pmid=22790015 |doi=10.1038/modpathol.2012.118 |url=}}</ref>  Bowtell<ref name="pmid20944665">{{cite journal |vauthors=Bowtell DD |title=The genesis and evolution of high-grade serous ovarian cancer |journal=Nat. Rev. Cancer |volume=10 |issue=11 |pages=803–8 |year=2010 |pmid=20944665 |doi=10.1038/nrc2946 |url=}}</ref> reviewed the literature indicating that deficient homologous recombination repair caused by BRCA1 deficiency is tumorigenic.  In particular this deficiency initiates a cascade of molecular events that sculpt the evolution of high-grade serous ovarian cancer and dictate its response to therapy.  Especially noted was that BRCA1 deficiency could be the cause of tumorigenesis whether due to BRCA1 mutation or any other event that causes a deficiency of BRCA1 expression.
+*Similarly, BRCA1 expression is low in the majority (55%) of sporadic [[Ovarian cancer#Epithelial carcinoma|epithelial ovarian cancers (EOCs)]] where EOCs are the most common type of ovarian cancer, representing approximately 90% of ovarian cancers.<ref name="Sun">{{cite journal |vauthors=Sun C, Li N, Yang Z, Zhou B, He Y, Weng D, Fang Y, Wu P, Chen P, Yang X, Ma D, Zhou J, Chen G |title=miR-9 regulation of BRCA1 and ovarian cancer sensitivity to cisplatin and PARP inhibition |journal=J. Natl. Cancer Inst. |volume=105 |issue=22 |pages=1750–8 |year=2013 |pmid=24168967 |doi=10.1093/jnci/djt302 |url=}}</ref>
+*In [[Ovarian cancer#Serous carcinoma|serous ovarian carcinomas]], a sub-category constituting about 2/3 of EOCs, low BRCA1 expression occurs in more than 50% of cases.<ref name="pmid22790015">{{cite journal |vauthors=McMillen BD, Aponte MM, Liu Z, Helenowski IB, Scholtens DM, Buttin BM, Wei JJ |title=Expression analysis of MIR182 and its associated target genes in advanced ovarian carcinoma |journal=Mod. Pathol. |volume=25 |issue=12 |pages=1644–53 |year=2012 |pmid=22790015 |doi=10.1038/modpathol.2012.118 |url=}}</ref>
+*Bowtell<ref name="pmid20944665">{{cite journal |vauthors=Bowtell DD |title=The genesis and evolution of high-grade serous ovarian cancer |journal=Nat. Rev. Cancer |volume=10 |issue=11 |pages=803–8 |year=2010 |pmid=20944665 |doi=10.1038/nrc2946 |url=}}</ref> reviewed the literature indicating that deficient homologous recombination repair caused by BRCA1 deficiency is tumorigenic.
+*In particular this deficiency initiates a cascade of molecular events that sculpt the evolution of high-grade serous ovarian cancer and dictate its response to therapy.
+*Especially noted was that BRCA1 deficiency could be the cause of tumorigenesis whether due to BRCA1 mutation or any other event that causes a deficiency of BRCA1 expression.
 =====Mutation of ''BRCA1'' in breast and ovarian cancer=====
-Only about 3%–8% of all women with breast cancer carry a mutation in BRCA1 or BRCA2.<ref name="pmid9653432">{{cite journal |vauthors=Brody LC, Biesecker BB |title=Breast cancer susceptibility genes. BRCA1 and BRCA2 |journal=Medicine (Baltimore) |volume=77 |issue=3 |pages=208–26 |year=1998 |pmid=9653432 |doi= 10.1097/00005792-199805000-00006|url=}}</ref>  Similarly, ''BRCA1'' mutations are only seen in about 18% of ovarian cancers (13% germline mutations and 5% somatic mutations).<ref name="pmid24240112">{{cite journal |vauthors=Pennington KP, Walsh T, Harrell MI, Lee MK, Pennil CC, Rendi MH, Thornton A, Norquist BM, Casadei S, Nord AS, Agnew KJ, Pritchard CC, Scroggins S, Garcia RL, King MC, Swisher EM |title=Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas |journal=Clin. Cancer Res. |volume=20 |issue=3 |pages=764–75 |year=2014 |pmid=24240112 |pmc=3944197 |doi=10.1158/1078-0432.CCR-13-2287 |url=}}</ref>
+*Only about 3%–8% of all women with breast cancer carry a mutation in BRCA1 or BRCA2.<ref name="pmid9653432">{{cite journal |vauthors=Brody LC, Biesecker BB |title=Breast cancer susceptibility genes. BRCA1 and BRCA2 |journal=Medicine (Baltimore) |volume=77 |issue=3 |pages=208–26 |year=1998 |pmid=9653432 |doi= 10.1097/00005792-199805000-00006|url=}}</ref>  Similarly, ''BRCA1'' mutations are only seen in about 18% of ovarian cancers (13% germline mutations and 5% somatic mutations).<ref name="pmid24240112">{{cite journal |vauthors=Pennington KP, Walsh T, Harrell MI, Lee MK, Pennil CC, Rendi MH, Thornton A, Norquist BM, Casadei S, Nord AS, Agnew KJ, Pritchard CC, Scroggins S, Garcia RL, King MC, Swisher EM |title=Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas |journal=Clin. Cancer Res. |volume=20 |issue=3 |pages=764–75 |year=2014 |pmid=24240112 |pmc=3944197 |doi=10.1158/1078-0432.CCR-13-2287 |url=}}</ref>
-Thus, while BRCA1 expression is low in the majority of these cancers, ''BRCA1'' mutation is not a major cause of reduced expression.
+*Thus, while BRCA1 expression is low in the majority of these cancers, ''BRCA1'' mutation is not a major cause of reduced expression.
 =====''BRCA1'' promoter hypermethylation in breast and ovarian cancer=====
-''BRCA1'' [[DNA methylation|promoter hypermethylation]] was present in only 13% of unselected primary breast carcinomas.<ref name="pmid10749912">{{cite journal |vauthors=Esteller M, Silva JM, Dominguez G, Bonilla F, Matias-Guiu X, Lerma E, Bussaglia E, Prat J, Harkes IC, Repasky EA, Gabrielson E, Schutte M, Baylin SB, Herman JG|authorlink13=Stephen B. Baylin|authorlink14=James G. Herman |title=Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors |journal=J. Natl. Cancer Inst. |volume=92 |issue=7 |pages=564–9 |year=2000 |pmid=10749912 |doi= 10.1093/jnci/92.7.564|url=}}</ref>  Similarly, ''BRCA1'' promoter hypermethylation was present in only 5% to 15% of EOC cases.<ref name="Sun" />
+*''BRCA1'' [[DNA methylation|promoter hypermethylation]] was present in only 13% of unselected primary breast carcinomas.<ref name="pmid10749912">{{cite journal |vauthors=Esteller M, Silva JM, Dominguez G, Bonilla F, Matias-Guiu X, Lerma E, Bussaglia E, Prat J, Harkes IC, Repasky EA, Gabrielson E, Schutte M, Baylin SB, Herman JG|authorlink13=Stephen B. Baylin|authorlink14=James G. Herman |title=Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors |journal=J. Natl. Cancer Inst. |volume=92 |issue=7 |pages=564–9 |year=2000 |pmid=10749912 |doi= 10.1093/jnci/92.7.564|url=}}</ref>  Similarly, ''BRCA1'' promoter hypermethylation was present in only 5% to 15% of EOC cases.<ref name="Sun" />
-Thus, while BRCA1 expression is low in these cancers, ''BRCA1'' promoter methylation is only a minor cause of reduced expression.
+*Thus, while BRCA1 expression is low in these cancers, ''BRCA1'' promoter methylation is only a minor cause of reduced expression.
 =====MicroRNA repression of BRCA1 in breast cancers=====
-There are a number of specific [[MicroRNA#DNA repair and cancer|microRNAs]], when overexpressed, that directly reduce expression of specific DNA repair proteins (see [[MicroRNA#DNA repair and cancer|MicroRNA section DNA repair and cancer]])  In the case of breast cancer, microRNA-182 (miR-182) specifically targets BRCA1.<ref name="Moskwa">{{cite journal |vauthors=Moskwa P, Buffa FM, Pan Y, Panchakshari R, Gottipati P, Muschel RJ, Beech J, Kulshrestha R, Abdelmohsen K, Weinstock DM, Gorospe M, Harris AL, Helleday T, Chowdhury D |title=miR-182-mediated downregulation of BRCA1 impacts DNA repair and sensitivity to PARP inhibitors |journal=Mol. Cell |volume=41 |issue=2 |pages=210–20 |year=2011 |pmid=21195000 |pmc=3249932 |doi=10.1016/j.molcel.2010.12.005 |url=}}</ref>  Breast cancers can be [[Breast cancer classification|classified]] based on receptor status or histology, with [[triple-negative breast cancer]] (15%–25% of breast cancers), [[Breast cancer#HER2 and cancer|HER2+]] (15%–30% of breast cancers), [[Estrogen receptor#Cancer|ER+]]/[[Progesterone receptor|PR+]] (about 70% of breast cancers), and [[Invasive lobular carcinoma]] (about 5%–10% of invasive breast cancer).  All four types of breast cancer were found to have an average of about 100-fold increase in miR-182, compared to normal breast tissue.<ref name="pmid23249749">{{cite journal |vauthors=Krishnan K, Steptoe AL, Martin HC, Wani S, Nones K, Waddell N, Mariasegaram M, Simpson PT, Lakhani SR, Gabrielli B, Vlassov A, Cloonan N, Grimmond SM |title=MicroRNA-182-5p targets a network of genes involved in DNA repair |journal=RNA |volume=19 |issue=2 |pages=230–42 |year=2013 |pmid=23249749 |pmc=3543090 |doi=10.1261/rna.034926.112 |url=}}</ref>  In breast cancer cell lines, there is an inverse correlation of BRCA1 protein levels with miR-182 expression.<ref name="Moskwa" /> Thus it appears that much of the reduction or absence of BRCA1 in high grade ductal breast cancers may be due to over-expressed miR-182.
+*There are a number of specific [[MicroRNA#DNA repair and cancer|microRNAs]], when overexpressed, that directly reduce expression of specific DNA repair proteins (see [[MicroRNA#DNA repair and cancer|MicroRNA section DNA repair and cancer]])  In the case of breast cancer, microRNA-182 (miR-182) specifically targets BRCA1.<ref name="Moskwa">{{cite journal |vauthors=Moskwa P, Buffa FM, Pan Y, Panchakshari R, Gottipati P, Muschel RJ, Beech J, Kulshrestha R, Abdelmohsen K, Weinstock DM, Gorospe M, Harris AL, Helleday T, Chowdhury D |title=miR-182-mediated downregulation of BRCA1 impacts DNA repair and sensitivity to PARP inhibitors |journal=Mol. Cell |volume=41 |issue=2 |pages=210–20 |year=2011 |pmid=21195000 |pmc=3249932 |doi=10.1016/j.molcel.2010.12.005 |url=}}</ref>
+*Almost all types of breast cancer were found to have an average of about 100-fold increase in miR-182, compared to normal breast tissue.<ref name="pmid23249749">{{cite journal |vauthors=Krishnan K, Steptoe AL, Martin HC, Wani S, Nones K, Waddell N, Mariasegaram M, Simpson PT, Lakhani SR, Gabrielli B, Vlassov A, Cloonan N, Grimmond SM |title=MicroRNA-182-5p targets a network of genes involved in DNA repair |journal=RNA |volume=19 |issue=2 |pages=230–42 |year=2013 |pmid=23249749 |pmc=3543090 |doi=10.1261/rna.034926.112 |url=}}</ref>
+*In breast cancer cell lines, there is an inverse correlation of BRCA1 protein levels with miR-182 expression.<ref name="Moskwa" />
+*'''Thus it appears that much of the reduction or absence of BRCA1 in high grade ductal breast cancers may be due to over-expressed miR-182.'''
-In addition to miR-182, a pair of almost identical microRNAs, miR-146a and miR-146b-5p, also repress BRCA1 expression.  These two microRNAs are over-expressed in triple-negative tumors and their over-expression results in BRCA1 inactivation.<ref name="pmid21472990">{{cite journal |vauthors=Garcia AI, Buisson M, Bertrand P, Rimokh R, Rouleau E, Lopez BS, Lidereau R, Mikaélian I, Mazoyer S |title=Down-regulation of BRCA1 expression by miR-146a and miR-146b-5p in triple negative sporadic breast cancers |journal=EMBO Mol Med |volume=3 |issue=5 |pages=279–90 |year=2011 |pmid=21472990 |pmc=3377076 |doi=10.1002/emmm.201100136 |url=}}</ref>  Thus, miR-146a and/or miR-146b-5p may also contribute to reduced expression of BRCA1 in these triple-negative breast cancers.
+*In addition to miR-182, a pair of almost identical microRNAs, miR-146a and miR-146b-5p, also repress BRCA1 expression.
+*These two microRNAs are over-expressed in triple-negative tumors and their over-expression results in BRCA1 inactivation.<ref name="pmid21472990">{{cite journal |vauthors=Garcia AI, Buisson M, Bertrand P, Rimokh R, Rouleau E, Lopez BS, Lidereau R, Mikaélian I, Mazoyer S |title=Down-regulation of BRCA1 expression by miR-146a and miR-146b-5p in triple negative sporadic breast cancers |journal=EMBO Mol Med |volume=3 |issue=5 |pages=279–90 |year=2011 |pmid=21472990 |pmc=3377076 |doi=10.1002/emmm.201100136 |url=}}</ref>
+*'''Thus, miR-146a and/or miR-146b-5p may also contribute to reduced expression of BRCA1 in these triple-negative breast cancers.'''
 =====MicroRNA repression of BRCA1 in ovarian cancers=====
-In both [[Ovarian cancer#Pathophysiology|serous tubal intraepithelial carcinoma]] (the precursor lesion to [[Ovarian cancer#Pathophysiology|high grade serous ovarian carcinoma (HG-SOC)]]), and in HG-SOC itself, miR-182 is overexpressed in about 70% of cases.<ref name="Liu">{{cite journal |vauthors=Liu Z, Liu J, Segura MF, Shao C, Lee P, Gong Y, Hernando E, Wei JJ |title=MiR-182 overexpression in tumourigenesis of high-grade serous ovarian carcinoma |journal=J. Pathol. |volume=228 |issue=2 |pages=204–15 |year=2012 |pmid=22322863 |doi=10.1002/path.4000 |url=}}</ref>  In cells with over-expressed miR-182, BRCA1 remained low, even after exposure to ionizing radiation (which normally raises BRCA1 expression).<ref name="Liu" />  Thus much of the reduced or absent BRCA1 in HG-SOC may be due to over-expressed miR-182.
+*In both [[Ovarian cancer#Pathophysiology|serous tubal intraepithelial carcinoma]] (the precursor lesion to [[Ovarian cancer#Pathophysiology|high grade serous ovarian carcinoma (HG-SOC)]]), and in HG-SOC itself, miR-182 is overexpressed in about 70% of cases.<ref name="Liu">{{cite journal |vauthors=Liu Z, Liu J, Segura MF, Shao C, Lee P, Gong Y, Hernando E, Wei JJ |title=MiR-182 overexpression in tumourigenesis of high-grade serous ovarian carcinoma |journal=J. Pathol. |volume=228 |issue=2 |pages=204–15 |year=2012 |pmid=22322863 |doi=10.1002/path.4000 |url=}}</ref>
+*In cells with over-expressed miR-182, BRCA1 remained low, even after exposure to ionizing radiation (which normally raises BRCA1 expression).<ref name="Liu" />
+*Thus much of the reduced or absent BRCA1 in HG-SOC may be due to over-expressed miR-182.
-Another microRNA known to reduce expression of BRCA1 in ovarian cancer cells is miR-9.<ref name="Sun" />  Among 58 tumors from patients with stage IIIC or stage IV serous ovarian cancers (HG-SOG), an inverse correlation was found between expressions of miR-9 and BRCA1,<ref name="Sun" /> so that increased miR-9 may also contribute to reduced expression of BRCA1 in these ovarian cancers.
+*Another microRNA known to reduce expression of BRCA1 in ovarian cancer cells is miR-9.<ref name="Sun" />  Among 58 tumors from patients with stage IIIC or stage IV serous ovarian cancers (HG-SOG), an inverse correlation was found between expressions of miR-9 and BRCA1,<ref name="Sun" /> so that increased miR-9 may also contribute to reduced expression of BRCA1 in these ovarian cancers.
 {{Dynamic list}}
@@ Line 121: / Line 250: @@
 ===BRCA2===
-BRCA2 and [[BRCA1]] are normally expressed in the cells of [[breast]] and other tissue, where they help repair damaged [[DNA]] or destroy cells if DNA cannot be repaired. They are involved in the repair of [[chromosome|chromosomal]] damage with an important role in the error-free [[DNA repair|repair of DNA]] double strand breaks.<ref name="Friedenson2007">{{cite journal | vauthors = Friedenson B | title = The BRCA1/2 pathway prevents hematologic cancers in addition to breast and ovarian cancers. | journal = BMC Cancer | volume = 7 | pages = 152–162 | date = August 2007 | pmid = 17683622 | pmc = 1959234 | doi = 10.1186/1471-2407-7-152 }}</ref><ref name="scivee.tv">{{cite web | url = http://www.scivee.tv/node/6090 | title = Breast cancer genes protect against some leukemias and lymphomas | author = Friedenson B | date = 2008-06-08  | format = video | publisher = SciVee }}</ref> If BRCA1 or BRCA2 itself is damaged by a [[BRCA mutation]], damaged DNA is not repaired properly, and this increases the risk for [[breast cancer]].<ref name="urlBreast and Ovarian Cancer Genetic Screening">{{cite web | url = http://www.pamf.org/health/guidelines/geneticscreening.html | title = Breast and Ovarian Cancer Genetic Screening | publisher = Palo Alto Medical Foundation | pages = | accessdate = 2008-10-11| archiveurl= https://web.archive.org/web/20081004080235/http://www.pamf.org/health/guidelines/geneticscreening.html| archivedate= 4 October 2008 <!--DASHBot-->| deadurl= no}}</ref><ref name="pmid17683622">{{cite journal | vauthors = Friedenson B | title = The BRCA1/2 pathway prevents hematologic cancers in addition to breast and ovarian cancers | journal = BMC Cancer | volume = 7 | page = 152 | year = 2007 | pmid = 17683622 | pmc = 1959234 | doi = 10.1186/1471-2407-7-152 }}</ref> ''BRCA1'' and ''BRCA2'' have been described as "breast cancer susceptibility genes" and "breast cancer susceptibility proteins".  The predominant allele has a normal tumor suppressive function whereas high [[penetrance]] mutations in these genes cause a loss of tumor suppressive function, which correlates with an increased risk of breast cancer.<ref name="O'Donovan_2010">{{cite journal | vauthors = O'Donovan PJ, Livingston DM | title = BRCA1 and BRCA2: breast/ovarian cancer susceptibility gene products and participants in DNA double-strand break repair | journal = Carcinogenesis | volume = 31 | issue = 6 | pages = 961–7 | year = April 2010 | pmid = 20400477 | doi = 10.1093/carcin/bgq069 }}</ref>
+*BRCA2 and [[BRCA1]] are normally expressed in the cells of [[breast]] and other tissue, where they help repair damaged [[DNA]] or destroy cells if DNA cannot be repaired.
+*They are involved in the repair of [[chromosome|chromosomal]] damage with an important role in the error-free [[DNA repair|repair of DNA]] double strand breaks.<ref name="Friedenson2007">{{cite journal | vauthors = Friedenson B | title = The BRCA1/2 pathway prevents hematologic cancers in addition to breast and ovarian cancers. | journal = BMC Cancer | volume = 7 | pages = 152–162 | date = August 2007 | pmid = 17683622 | pmc = 1959234 | doi = 10.1186/1471-2407-7-152 }}</ref><ref name="scivee.tv">{{cite web | url = http://www.scivee.tv/node/6090 | title = Breast cancer genes protect against some leukemias and lymphomas | author = Friedenson B | date = 2008-06-08  | format = video | publisher = SciVee }}</ref>
+*If BRCA1 or BRCA2 itself is damaged by a [[BRCA mutation]], damaged DNA is not repaired properly, and this increases the risk for [[breast cancer]].<ref name="urlBreast and Ovarian Cancer Genetic Screening">{{cite web | url = http://www.pamf.org/health/guidelines/geneticscreening.html | title = Breast and Ovarian Cancer Genetic Screening | publisher = Palo Alto Medical Foundation | pages = | accessdate = 2008-10-11| archiveurl= https://web.archive.org/web/20081004080235/http://www.pamf.org/health/guidelines/geneticscreening.html| archivedate= 4 October 2008 <!--DASHBot-->| deadurl= no}}</ref><ref name="pmid17683622">{{cite journal | vauthors = Friedenson B | title = The BRCA1/2 pathway prevents hematologic cancers in addition to breast and ovarian cancers | journal = BMC Cancer | volume = 7 | page = 152 | year = 2007 | pmid = 17683622 | pmc = 1959234 | doi = 10.1186/1471-2407-7-152 }}</ref>
+*''BRCA1'' and ''BRCA2'' have been described as "breast cancer susceptibility genes" and "breast cancer susceptibility proteins".
+*The predominant allele has a normal tumor suppressive function whereas high [[penetrance]] mutations in these genes cause a loss of tumor suppressive function, which correlates with an increased risk of breast cancer.<ref name="O'Donovan_2010">{{cite journal | vauthors = O'Donovan PJ, Livingston DM | title = BRCA1 and BRCA2: breast/ovarian cancer susceptibility gene products and participants in DNA double-strand break repair | journal = Carcinogenesis | volume = 31 | issue = 6 | pages = 961–7 | year = April 2010 | pmid = 20400477 | doi = 10.1093/carcin/bgq069 }}</ref>
-The BRCA2 gene is located on the long (q) arm of [[chromosome 13 (human)|chromosome 13]] at position 12.3 (13q12.3).<ref name="pmid8091231">{{cite journal | vauthors = Wooster R, Neuhausen SL, Mangion J, Quirk Y, Ford D, Collins N, Nguyen K, Seal S, Tran T, Averill D | title = Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13 | journal = Science | volume = 265 | issue = 5181 | pages = 2088–90 | date = September 1994 | pmid = 8091231 | doi = 10.1126/science.8091231 | bibcode = 1994Sci...265.2088W }}</ref> The human reference BRCA 2 gene contains 27 exons, and the cDNA has  10,254 base pairs<ref name="EntrezGene">{{cite web | url = https://www.ncbi.nlm.nih.gov/gene/675 | title = BRCA2 breast cancer 2, early onset [Homo sapiens] | work = EntrezGene | publisher = National Center for Biotechnology Information, U.S. National Library of Medicine }}</ref> coding for a protein of 3418 amino acids.<ref name="UniProt_P51587">{{cite web | url = https://www.uniprot.org/uniprot/P51587 | title = Breast cancer type 2 susceptibility protein - Homo sapiens (Human) | work = P51587 | publisher = UniProt }}</ref><ref name="Williams-Jones_2002">{{cite thesis | type = Ph.D. | author = Williams-Jones B | title = Genetic testing for sale: Implications of commercial brca testing in Canada | publisher = The University of British Columbia | year = 2002 }}</ref>
+*The BRCA2 gene is located on the long (q) arm of [[chromosome 13 (human)|chromosome 13]] at position 12.3 (13q12.3).<ref name="pmid8091231">{{cite journal | vauthors = Wooster R, Neuhausen SL, Mangion J, Quirk Y, Ford D, Collins N, Nguyen K, Seal S, Tran T, Averill D | title = Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13 | journal = Science | volume = 265 | issue = 5181 | pages = 2088–90 | date = September 1994 | pmid = 8091231 | doi = 10.1126/science.8091231 | bibcode = 1994Sci...265.2088W }}</ref> The human reference BRCA 2 gene contains 27 exons, and the cDNA has  10,254 base pairs<ref name="EntrezGene">{{cite web | url = https://www.ncbi.nlm.nih.gov/gene/675 | title = BRCA2 breast cancer 2, early onset [Homo sapiens] | work = EntrezGene | publisher = National Center for Biotechnology Information, U.S. National Library of Medicine }}</ref> coding for a protein of 3418 amino acids.<ref name="UniProt_P51587">{{cite web | url = https://www.uniprot.org/uniprot/P51587 | title = Breast cancer type 2 susceptibility protein - Homo sapiens (Human) | work = P51587 | publisher = UniProt }}</ref><ref name="Williams-Jones_2002">{{cite thesis | type = Ph.D. | author = Williams-Jones B | title = Genetic testing for sale: Implications of commercial brca testing in Canada | publisher = The University of British Columbia | year = 2002 }}</ref>
-Certain variations of the BRCA2 gene increase risks for [[breast cancer]] as part of a [[hereditary breast-ovarian cancer syndrome]]. Researchers have identified hundreds of mutations in the BRCA2 gene, many of which cause an increased risk of cancer. BRCA2 mutations are usually insertions or deletions of a small number of DNA base pairs in the gene. As a result of these mutations, the protein product of the BRCA2 gene is abnormal, and does not function properly. Researchers believe that the defective BRCA2 protein is unable to fix DNA damage that occurs throughout the genome.  As a result, there is an increase in mutations due to error-prone [[DNA repair#Translesion synthesis|translesion synthesis]] past un-repaired DNA damage, and some of these mutations can cause cells to divide in an uncontrolled way and form a tumor.
+*Certain variations of the BRCA2 gene increase risks for [[breast cancer]] as part of a [[hereditary breast-ovarian cancer syndrome]].
+*Researchers have identified hundreds of mutations in the BRCA2 gene, many of which cause an increased risk of cancer. BRCA2 mutations are usually insertions or deletions of a small number of DNA base pairs in the gene.
+*As a result of these mutations, the protein product of the BRCA2 gene is abnormal, and does not function properly. Researchers believe that the defective BRCA2 protein is unable to fix DNA damage that occurs throughout the genome.
+*As a result, there is an increase in mutations due to error-prone [[DNA repair#Translesion synthesis|translesion synthesis]] past un-repaired DNA damage, and some of these mutations can cause cells to divide in an uncontrolled way and form a tumor.
-In general, strongly inherited gene mutations (including mutations in BRCA2) account for only 5-10% of breast cancer cases; the specific risk of getting breast or other cancer for anyone carrying a BRCA2 mutation depends on many factors.<ref>{{cite web | URL = http://www.cancer.gov/cancertopics/pdq/genetics/breast-and-ovarian/HealthProfessional/page2| title = High-Penetrance Breast and/or Ovarian Cancer Susceptibility Genes | publisher=National Cancer Institute | accessdate = 19 April 2019}}</ref>
+*In general, strongly inherited gene mutations (including mutations in BRCA2) account for only 5-10% of breast cancer cases; the specific risk of getting breast or other cancer for anyone carrying a BRCA2 mutation depends on many factors.<ref>{{cite web | URL = http://www.cancer.gov/cancertopics/pdq/genetics/breast-and-ovarian/HealthProfessional/page2| title = High-Penetrance Breast and/or Ovarian Cancer Susceptibility Genes | publisher=National Cancer Institute | accessdate = 19 April 2019}}</ref>
-All germline BRCA2 mutations identified to date have been inherited, suggesting the possibility of a large "founder" effect in which a certain mutation is common to a well-defined population group and can theoretically be traced back to a common ancestor. Given the complexity of mutation screening for BRCA2, these common mutations may simplify the methods required for mutation screening in certain populations. Analysis of mutations that occur with high frequency also permits the study of their clinical expression.<ref name="Lacroix2005">{{cite journal | vauthors = Lacroix M, Leclercq G | title = The "portrait" of hereditary breast cancer | journal = Breast Cancer Research and Treatment | volume = 89 | issue = 3 | pages = 297–304 | year = 2005 | pmid = 15754129 | doi = 10.1007/s10549-004-2172-4 }}</ref> A striking example of a founder mutation is found in Iceland, where a single BRCA2 (999del5) mutation accounts for virtually all breast/ovarian cancer families.<ref name="Thorlacius1996">{{cite journal | vauthors = Thorlacius S, Olafsdottir G, Tryggvadottir L, Neuhausen S, Jonasson JG, Tavtigian SV, Tulinius H, Ogmundsdottir HM, Eyfjörd JE | title = A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes | journal = Nature Genetics | volume = 13 | issue = 1 | pages = 117–119 | year = 1996 | pmid = 8673089 | doi = 10.1038/ng0596-117 }}</ref><ref name="Thorlacius1997">{{cite journal | vauthors = Thorlacius S, Sigurdsson S, Bjarnadottir H, Olafsdottir G, Jonasson JG, Tryggvadottir L, Tulinius H, Eyfjörd JE | title = Study of a single BRCA2 mutation with high carrier frequency in a small population | journal = American Journal of Human Genetics | volume = 60 | issue = 5 | pages = 1079–1085 | year = 1997 | pmid = 9150155 | pmc = 1712443 | doi =  }}</ref> This frame-shift mutation leads to a highly truncated protein product. In a large study examining hundreds of cancer and control individuals, this 999del5 mutation was found in 0.6% of the general population. Of note, while 72% of patients who were found to be carriers had a moderate or strong family history of breast cancer, 28% had little or no family history of the disease. This strongly suggests the presence of modifying genes that affect the phenotypic expression of this mutation, or possibly the interaction of the BRCA2 mutation with environmental factors. Additional examples of founder mutations in BRCA2 are given in the table below.
+*All germline BRCA2 mutations identified to date have been inherited, suggesting the possibility of a large "founder" effect in which a certain mutation is common to a well-defined population group and can theoretically be traced back to a common ancestor.
+*Given the complexity of mutation screening for BRCA2, these common mutations may simplify the methods required for mutation screening in certain populations
+*. Analysis of mutations that occur with high frequency also permits the study of their clinical expression.<ref name="Lacroix2005">{{cite journal | vauthors = Lacroix M, Leclercq G | title = The "portrait" of hereditary breast cancer | journal = Breast Cancer Research and Treatment | volume = 89 | issue = 3 | pages = 297–304 | year = 2005 | pmid = 15754129 | doi = 10.1007/s10549-004-2172-4 }}</ref> A
+*striking example of a founder mutation is found in Iceland, where a single BRCA2 (999del5) mutation accounts for virtually all breast/ovarian cancer families.<ref name="Thorlacius1996">{{cite journal | vauthors = Thorlacius S, Olafsdottir G, Tryggvadottir L, Neuhausen S, Jonasson JG, Tavtigian SV, Tulinius H, Ogmundsdottir HM, Eyfjörd JE | title = A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes | journal = Nature Genetics | volume = 13 | issue = 1 | pages = 117–119 | year = 1996 | pmid = 8673089 | doi = 10.1038/ng0596-117 }}</ref><ref name="Thorlacius1997">{{cite journal | vauthors = Thorlacius S, Sigurdsson S, Bjarnadottir H, Olafsdottir G, Jonasson JG, Tryggvadottir L, Tulinius H, Eyfjörd JE | title = Study of a single BRCA2 mutation with high carrier frequency in a small population | journal = American Journal of Human Genetics | volume = 60 | issue = 5 | pages = 1079–1085 | year = 1997 | pmid = 9150155 | pmc = 1712443 | doi =  }}</ref>
+*This frame-shift mutation leads to a highly truncated protein product. In a large study examining hundreds of cancer and control individuals, this 999del5 mutation was found in 0.6% of the general population
+*. Of note, while 72% of patients who were found to be carriers had a moderate or strong family history of breast cancer, 28% had little or no family history of the disease.
+*This strongly suggests the presence of modifying genes that affect the phenotypic expression of this mutation, or possibly the interaction of the BRCA2 mutation with environmental factors. Additional examples of founder mutations in BRCA2 are given in the table below.
 {{Dynamic list}}
@@ Line 163: / Line 305: @@
 |-
 | Swedish || 4486delG ||<ref name="Neuhausen2000">{{cite journal | vauthors = Neuhausen SL | title = Founder populations and their uses for breast cancer genetics | journal = Cancer Research | volume = 2 | issue = 2 | pages = 77–81 | year = 2000 | pmid = 11250694 | pmc = 139426 | doi = 10.1186/bcr36 }}</ref>
 |}
+===Commercial BRCA mutation tests===
-==HER2==
+*The sensitivity of commercial BRCA mutation tests like 23andMe is debated.
-*HER2 is a member of the human [[epidermal growth factor receptor]] (HER/EGFR/ERBB) family.
+*For example, 23andMe’s testing formula is based on solely three genetic variants, most prevalent among Ashkenazi Jews, while most people carry other mutations of the gene.
-*[[Gene duplication|Amplification]] or over-expression of this [[oncogene]] has been shown to play an important role in the development and progression of certain aggressive types of [[breast cancer]].
+*This will result in false negative results.
-*In recent years the protein has become an important [[Biomarker (medicine)|biomarker]] and target of therapy for approximately 30% of [[breast cancer]] patients.<ref name="pmid23320171" /> HER2 has several names among them are:
+*23andMe is a commercial BRCA1 screening test, with more than 10 million customers.
+*Even if only a small percentage take the test, that’s thousands who could be misled.
-:*'''Receptor tyrosine-protein kinase erbB-2'''
+*As accurately stated by Prof. Mary-Claire King, who discovered the BRCA1, “The F.D.A. should not have permitted this out-of-date approach to be used for medical purposes. Misleading, falsely reassuring results from their incomplete testing can cost women’s lives.”
-:* '''CD340''' ([[cluster of differentiation]] 340)
-:* '''proto-oncogene Neu'''
-:* '''Erbb2''' (rodent), or '''ERBB2''' (human)
-:* '''''HER2''''' (from '''human epidermal growth factor receptor 2''')
-:* '''''HER2/neu''''' <ref>{{Cite web|url=https://www.ncbi.nlm.nih.gov/gene/2064|title=ERBB2 erb-b2 receptor tyrosine kinase 2 [Homo sapiens (human)] - Gene - NCBI|website=www.ncbi.nlm.nih.gov|access-date=2016-06-14}}</ref><ref>{{Cite web|url=https://ghr.nlm.nih.gov/gene/ERBB2|title=ERBB2|last=Reference|first=Genetics Home|website=Genetics Home Reference|access-date=2016-06-19}}</ref><ref>{{Cite book|url=https://books.google.com/books?id=xZoXBgAAQBAJ|title=Noninvasive Molecular Markers in Gynecologic Cancers|last=Barh|first=Debmalya|last2=Gunduz|first2=Mehmet | name-list-format = vanc |date=2015-01-22|publisher=CRC Press|page=427|isbn=9781466569393 }}</ref>
-===Signaling pathways===
-*Signaling pathways activated by HER2 include:<ref name="pmid19887469">{{cite journal | vauthors = Roy V, Perez EA | title = Beyond trastuzumab: small molecule tyrosine kinase inhibitors in HER-2-positive breast cancer | journal = The Oncologist | volume = 14 | issue = 11 | pages = 1061–9 | date = November 2009 | pmid = 19887469 | doi = 10.1634/theoncologist.2009-0142 }}</ref>
-:* [[mitogen-activated protein kinase]] (MAPK)
-:* [[phosphoinositide 3-kinase]] (PI3K/Akt)
-:* [[phospholipase C]] γ
-:* [[protein kinase C]] (PKC)
-:* [[STAT protein|Signal transducer and activator of transcription]] (STAT)
-*In a nutshell, signaling through the ErbB family of receptors promotes cell proliferation and opposes [[apoptosis]], and therefore must be tightly regulated to prevent uncontrolled cell growth from occurring.
-=== Cancer biopsy ===
-HER2 testing is performed in breast cancer patients to assess prognosis and to determine suitability for trastuzumab therapy. It is important that trastuzumab is restricted to HER2-positive individuals as it is expensive and has been associated with cardiac toxicity.<ref name="pmid17687157">{{cite journal | vauthors = Telli ML, Hunt SA, Carlson RW, Guardino AE | title = Trastuzumab-related cardiotoxicity: calling into question the concept of reversibility | journal = Journal of Clinical Oncology | volume = 25 | issue = 23 | pages = 3525–33 | date = August 2007 | pmid = 17687157 | doi = 10.1200/JCO.2007.11.0106 }}</ref> For HER2-negative tumours, the risks of trastuzumab clearly outweigh the benefits.
-Tests are usually performed on [[biopsy]] samples obtained by either [[fine-needle aspiration]],  core needle biopsy, [[vacuum-assisted breast biopsy]], or surgical excision. [[Immunohistochemistry]] is used to measure the amount of HER2 protein present in the sample. Examples of this assay include HercepTest, Dako, Glostrup, and Denmark. The sample is given a score based on the cell membrane staining pattern. Specimens with equivocal IHC results should then be validated using [[fluorescence in situ hybridisation]] (FISH). FISH can be used to measure the number of copies of the gene which are present and is thought to be more reliable than IHC.<ref>{{cite book | vauthors = Giuliano AE, Hurvitz SA | chapter = Breast Disorder | veditors = Papadakis MA, McPhee SJ, Rabow MW | title = Current Medical Diagnosis & Treatment | year = 2019 | location = New York, NY | publisher = McGraw-Hill }}</ref>
-=== Serum ===
-The extracellular domain of HER2 can be shed from the surface of tumour cells and enter the circulation. Measurement of serum HER2 by enzyme-linked immunosorbent assay ([[ELISA]]) offers a far less invasive method of determining HER2 status than a biopsy and consequently has been extensively investigated. Results so far have suggested that changes in serum HER2 concentrations may be useful in predicting response to trastuzumab therapy.<ref name="pmid18661530">{{cite journal | vauthors = Ali SM, Carney WP, Esteva FJ, Fornier M, Harris L, Köstler WJ, Lotz JP, Luftner D, Pichon MF, Lipton A | title = Serum HER-2/neu and relative resistance to trastuzumab-based therapy in patients with metastatic breast cancer | journal = Cancer | volume = 113 | issue = 6 | pages = 1294–301 | date = September 2008 | pmid = 18661530 | doi = 10.1002/cncr.23689 }}</ref> However, its ability to determine eligibility for trastuzumab therapy is less clear.<ref name="pmid19255335">{{cite journal | vauthors = Lennon S, Barton C, Banken L, Gianni L, Marty M, Baselga J, Leyland-Jones B | title = Utility of serum HER2 extracellular domain assessment in clinical decision making: pooled analysis of four trials of trastuzumab in metastatic breast cancer | journal = Journal of Clinical Oncology | volume = 27 | issue = 10 | pages = 1685–93 | date = April 2009 | pmid = 19255335 | doi = 10.1200/JCO.2008.16.8351 }}</ref>
-=== Cancer ===
-Amplification, also known as the over-expression of the ''ERBB2'' gene, occurs in approximately 15-30% of [[breast cancer]]s.<ref name="pmid23320171">{{cite journal | vauthors = Mitri Z, Constantine T, O'Regan R | title = The HER2 Receptor in Breast Cancer: Pathophysiology, Clinical Use, and New Advances in Therapy | journal = Chemotherapy Research and Practice | volume = 2012 | issue =  | pages = 743193 | year = 2012 | pmid = 23320171 | pmc = 3539433 | doi = 10.1155/2012/743193 }}</ref><ref name="pmid16236735">{{cite journal | vauthors = Burstein HJ | title = The distinctive nature of HER2-positive breast cancers | journal = The New England Journal of Medicine | volume = 353 | issue = 16 | pages = 1652–4 | date = October 2005 | pmid = 16236735 | doi = 10.1056/NEJMp058197 }}</ref> It is strongly associated with increased disease recurrence and a poor prognosis.<ref name="pmid17993237">{{cite journal | vauthors = Tan M, Yu D | title = Molecular mechanisms of erbB2-mediated breast cancer chemoresistance | journal = Advances in Experimental Medicine and Biology | volume = 608 | issue =  | pages = 119–29 | year = 2007 | pmid = 17993237 | doi = 10.1007/978-0-387-74039-3_9 | isbn = 978-0-387-74037-9 | series = Advances in Experimental Medicine and Biology }}</ref> Over-expression is also known to occur in ovarian,<ref>{{cite book |last1=Kumar |first=Vinay |last2=Abbas |first2=Abul |last3=Aster |first3=Jon | name-list-format = vanc | date=2013 |title=Robbins basic pathology |location=Philadelphia |publisher=Elsevier/Saunders |page=697 |isbn=9781437717815}}</ref> stomach, [[adenocarcinoma of the lung]]<ref>{{cite book |last1=Kumar |first=Vinay |last2=Abbas |first2=Abul |last3=Aster |first3=Jon | name-list-format = vanc | date=2013 |title=Robbins basic pathology |location=Philadelphia |publisher=Elsevier/Saunders |page=179 |isbn=9781437717815}}</ref>  and aggressive forms of uterine cancer, such as uterine serous [[endometrial carcinoma]],<ref>{{cite journal | vauthors = Santin AD, Bellone S, Roman JJ, McKenney JK, Pecorelli S | title = Trastuzumab treatment in patients with advanced or recurrent endometrial carcinoma overexpressing HER2/neu | journal = International Journal of Gynaecology and Obstetrics | volume = 102 | issue = 2 | pages = 128–31 | date = August 2008 | pmid = 18555254 | doi = 10.1016/j.ijgo.2008.04.008 }}</ref><ref name="Buza2014">{{cite journal | vauthors = Buza N, Roque DM, Santin AD | title = HER2/neu in Endometrial Cancer: A Promising Therapeutic Target With Diagnostic Challenges | journal = Archives of Pathology & Laboratory Medicine | volume = 138 | issue = 3 | pages = 343–50 | date = March 2014 | pmid = 24576030 | doi = 10.5858/arpa.2012-0416-RA }}</ref> e.g. HER-2 is over-expressed in approximately 7-34% of patients with gastric cancer<ref name="Rüschoff2012">{{cite journal | vauthors = Rüschoff J, Hanna W, Bilous M, Hofmann M, Osamura RY, Penault-Llorca F, van de Vijver M, Viale G | title = HER2 testing in gastric cancer: a practical approach | journal = Modern Pathology | volume = 25 | issue = 5 | pages = 637–50 | date = May 2012 | pmid = 22222640 | doi = 10.1038/modpathol.2011.198 }}</ref><ref name="pmid21556317">{{cite journal | vauthors = Meza-Junco J, Au HJ, Sawyer MB | title = Critical appraisal of trastuzumab in treatment of advanced stomach cancer | journal = Cancer Management and Research | volume = 3 | issue = 3 | pages = 57–64 | year = 2011 | pmid = 21556317 | pmc = 3085240 | doi = 10.2147/CMAR.S12698 }}</ref> and in 30% of salivary duct carcinomas.<ref>{{cite journal | vauthors = Chiosea SI, Williams L, Griffith CC, Thompson LD, Weinreb I, Bauman JE, Luvison A, Roy S, Seethala RR, Nikiforova MN | title = Molecular characterization of apocrine salivary duct carcinoma | journal = The American Journal of Surgical Pathology | volume = 39 | issue = 6 | pages = 744–52 | date = June 2015 | pmid = 25723113 | doi = 10.1097/PAS.0000000000000410 }}</ref>
-HER2 is colocalised and most of the time, coamplified with the gene [[GRB7]], which is a proto-oncogene associated with breast, testicular germ cell, gastric, and eosophageal tumours.
-HER2 proteins have been shown to form clusters in cell membranes that may play a role in tumorigenesis.<ref name="pmid10318765">{{cite journal | vauthors = Nagy P, Jenei A, Kirsch AK, Szöllosi J, Damjanovich S, Jovin TM | title = Activation-dependent clustering of the erbB2 receptor tyrosine kinase detected by scanning near-field optical microscopy | journal = Journal of Cell Science | volume = 112 | issue = 11 | pages = 1733–41 | date = June 1999 | pmid = 10318765 | doi =  }}</ref><ref name="pmid21118230">{{cite journal | vauthors = Kaufmann R, Müller P, Hildenbrand G, Hausmann M, Cremer C | title = Analysis of Her2/neu membrane protein clusters in different types of breast cancer cells using localization microscopy | journal = Journal of Microscopy | volume = 242 | issue = 1 | pages = 46–54 | date = April 2011 | pmid = 21118230 | doi = 10.1111/j.1365-2818.2010.03436.x }}</ref>
-Recent evidence has implicated HER2 signaling in resistance to the [[Epidermal growth factor receptor|EGFR]]-targeted cancer drug [[cetuximab]].<ref name="YonesakaZejnullahu2011">{{cite journal | vauthors = Yonesaka K, Zejnullahu K, Okamoto I, Satoh T, Cappuzzo F, Souglakos J, Ercan D, Rogers A, Roncalli M, Takeda M, Fujisaka Y, Philips J, Shimizu T, Maenishi O, Cho Y, Sun J, Destro A, Taira K, Takeda K, Okabe T, Swanson J, Itoh H, Takada M, Lifshits E, Okuno K, Engelman JA, Shivdasani RA, Nishio K, Fukuoka M, Varella-Garcia M, Nakagawa K, Jänne PA | display-authors = 6 | title = Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab | journal = Science Translational Medicine | volume = 3 | issue = 99 | pages = 99ra86 | date = September 2011 | pmid = 21900593 | pmc = 3268675 | doi = 10.1126/scitranslmed.3002442 }}</ref>
-=== Mutations ===
-Furthermore, diverse structural alterations have been identified that cause ligand-independent firing of this receptor, doing so in the absence of receptor over-expression. HER2 is found in a variety of tumours and some of these tumors carry point mutations in the sequence specifying the transmembrane domain of HER2. Substitution of a valine for a glutamic acid in the transmembrane domain can result in the constitutive dimerization of this protein in the absence of a ligand.<ref>{{cite journal | vauthors = Brandt-Rauf PW, Rackovsky S, Pincus MR | title = Correlation of the structure of the transmembrane domain of the neu oncogene-encoded p185 protein with its function | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 87 | issue = 21 | pages = 8660–4 | date = November 1990 | pmid = 1978329 | pmc = 55017 | doi = 10.1073/pnas.87.21.8660 | bibcode = 1990PNAS...87.8660B }}</ref>
-HER2 mutations have been found in [[non-small-cell lung cancer]]s (NSCLC) and can direct treatment.<ref name="Mazières2013">{{cite journal | vauthors = Mazières J, Peters S, Lepage B, Cortot AB, Barlesi F, Beau-Faller M, Besse B, Blons H, Mansuet-Lupo A, Urban T, Moro-Sibilot D, Dansin E, Chouaid C, Wislez M, Diebold J, Felip E, Rouquette I, Milia JD, Gautschi O | display-authors = 6 | title = Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives | journal = Journal of Clinical Oncology | volume = 31 | issue = 16 | pages = 1997–2003 | date = June 2013 | pmid = 23610105 | doi = 10.1200/JCO.2012.45.6095 }}</ref>
-=== As a drug target ===
-HER2 is the target of the [[monoclonal antibodies|monoclonal antibody]] [[trastuzumab]] (marketed as Herceptin).  Trastuzumab is effective only in cancers where HER2 is over-expressed. One year of trastuzumab therapy is recommended for all patients with HER2-positive breast cancer who are also receiving chemotherapy.<ref name="pmid25848335">{{cite journal | vauthors = Mates M, Fletcher GG, Freedman OC, Eisen A, Gandhi S, Trudeau ME, Dent SF | title = Systemic targeted therapy for her2-positive early female breast cancer: a systematic review of the evidence for the 2014 Cancer Care Ontario systemic therapy guideline | journal = Current Oncology | volume = 22 | issue = Suppl 1 | pages = S114-22 | date = March 2015 | pmid = 25848335 | pmc = 4381787 | doi = 10.3747/co.22.2322 }}</ref> Twelve months of trastuzumab therapy is optimal. Randomized trials have demonstrated no additional benefit beyond 12 months, whereas 6 months has been shown to be inferior to 12. Trastuzumab is administered intravenously weekly or every 3 weeks.<ref>{{Cite book|title=Harrison's Principles of Internal Medicine, 20th ed.|last=Jameson et al.|first=|publisher=McGraw-Hill Education|year=2018|isbn=978-1-259-64403-0|location=|pages=Chapter 75: Breast Cancer}}</ref>
-An important downstream effect of trastuzumab binding to HER2 is an increase in [[CDKN1B|p27]], a protein that halts cell proliferation.<ref name="Le_2005">{{cite journal | vauthors = Le XF, Pruefer F, Bast RC | title = HER2-targeting antibodies modulate the cyclin-dependent kinase inhibitor p27Kip1 via multiple signaling pathways | journal = Cell Cycle | volume = 4 | issue = 1 | pages = 87–95 | date = January 2005 | pmid = 15611642 | doi = 10.4161/cc.4.1.1360 }}</ref> Another monoclonal antibody, [[Pertuzumab]], which inhibits dimerisation of HER2 and HER3 receptors, was approved by the FDA for use in combination with trastuzumab in June 2012.
-As of November 2015, there are a number of ongoing and recently completed clinical trials of novel targeted agents for HER2+ metastatic breast cancer, e.g. [[margetuximab]].<ref>{{cite journal | vauthors = Jiang H, Rugo HS | title = Human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer: how the latest results are improving therapeutic options | journal = Therapeutic Advances in Medical Oncology | volume = 7 | issue = 6 | pages = 321–39 | date = November 2015 | pmid = 26557900 | pmc = 4622301 | doi = 10.1177/1758834015599389 }}</ref>
-Additionally, [[NeuVax]] ([[Galena Biopharma]]) is a peptide-based immunotherapy that directs "killer" [[T cell]]s to target and destroy cancer cells that express HER2. It has entered phase 3 clinical trials.
-It has been found that patients with ER+ ([[Estrogen receptor]] positive)/HER2+ compared with ER-/HER2+ breast cancers may actually benefit more from drugs that inhibit the [[PI3K/AKT/mTOR pathway|PI3K/AKT]] molecular pathway.<ref name="pmid19552798">{{cite journal | vauthors = Loi S, Sotiriou C, Haibe-Kains B, Lallemand F, Conus NM, Piccart MJ, Speed TP, McArthur GA | title = Gene expression profiling identifies activated growth factor signaling in poor prognosis (Luminal-B) estrogen receptor positive breast cancer | journal = BMC Medical Genomics | volume = 2 | issue =  | pages = 37 | year = 2009 | pmid = 19552798 | pmc = 2706265 | doi = 10.1186/1755-8794-2-37 | laysummary = https://www.sciencedaily.com/releases/2010/05/100506112557.htm | laysource = ScienceDaily }}</ref>
-Over-expression of HER2 can also be suppressed by the amplification of other genes. Research is currently being conducted to discover which genes may have this desired effect.
-The expression of HER2 is regulated by signaling through eostrogen receptors.  Normally, [[estradiol]] and [[tamoxifen]] acting through the eostrogen receptor down-regulate the expression of HER2.  However, when the ratio of the [[coactivator (genetics)|coactivator]] [[nuclear receptor coactivator 3|AIB-3]] exceeds that of the  [[corepressor (genetics)|corepressor]] [[PAX2]], the expression of HER2 is upregulated in the presence of tamoxifen, leading to tamoxifen-resistant [[breast cancer]].<ref name="urlCORDIS : News">{{cite web | url = http://cordis.europa.eu/fetch?CALLER=EN_NEWS&ACTION=D&SESSION=&RCN=30093 | title = Study sheds new light on tamoxifen resistance | authorlink = | date = 2008-11-13 | format = | work = Cordis News | publisher = Cordis | pages = | quote = | accessdate = 2008-11-14}}</ref><ref name="Hurtado1_2008">{{cite journal | vauthors = Hurtado A, Holmes KA, Geistlinger TR, Hutcheson IR, Nicholson RI, Brown M, Jiang J, Howat WJ, Ali S, Carroll JS | title = Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen | journal = Nature | volume = 456 | issue = 7222 | pages = 663–6 | date = December 2008 | pmid = 19005469 | pmc = 2920208 | doi = 10.1038/nature07483 | bibcode = 2008Natur.456..663H }}</ref>
-[[File:3D Dual Color Super Resolution Microscopy Cremer 2010.png|center|thumb|550px|3D Dual Color Super Resolution Microscopy Cremer 2010.png|Her2 and Her3 distribution on a breast cell, (3D Dual Colour Super Resolution Microscopy SPDMphymod / LIMON, marked with Alexa 488 and 568)]]
-{{Clear}}
-==Multiple gene panels==
-* '''Oncotype DX'''®
-* '''MammaPrint'''®
 ==Blood chemistry==
@@ Line 239: / Line 323: @@
 :*Increased levels could indicate that cancer has spread to the [[bone]].
 :*Tumor markers such as [[Ki-67 (Biology)|'''Ki67''']]
 ==References==
 {{Reflist|2}}