Breast cancer pathophysiology

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

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Overview

Genes involved in the pathogenesis of breast cancer include BRCA1, BRCA2 and p53. On microscopic histopathological analysis, minimal tubule formation, marked pleomorphism, and numerous mitotic figures are characteristic findings of breast cancer.

Pathophysiology

Physiology

The primary function of mammary glands is to nurture young by producing breast milk. The production of milk is called lactation. (While the mammary glands that produce milk are present in the male, they normally remain undeveloped.) The orb-like shape of breasts may help limit heat loss, as a fairly high temperature is required for the production of milk. Alternatively, one theory states that the shape of the human breast evolved in order to prevent infants from suffocating while feeding. Since human infants do not have a protruding jaw like human evolutionary ancestors and other primates, the infant’s nose might be blocked by a flat female chest while feeding. According to this theory, as the human jaw receded, the breasts became larger to compensate.

Milk production unrelated to pregnancy can also occur. This galactorrhea may be an adverse effect of some medicinal drugs (such as some antipsychotic medication), extreme physical stress or endocrine disorders. If it occurs in men it is called male lactation. Newborn babies are often capable of lactation because they receive the hormones prolactin and oxytocin via the mother's bloodstream, filtered through the placenta. This neonatal liquid is known colloquially as witch's milk.

Pathogenesis

• Majority of breast malignancies arise from epithelial cells and hence are carcinomas.
• Microscopic appearance and biologic behavior divide breast carcinomas to several diverse groups.
• Based upon the growth pattern and cytologic features of the lesions,the in situ carcinomas of the breast divide into ductal (also known as intraductal carcinoma) or lobular.
• Surprisingly their anatomic location within the mammary ductal-lobular system.

• The table below shows the invasive breast carcinomas several histologic subtypes; based on a series of 135,157 women with breast cancer reported to the SEER database o between 1992 and 2001.

Histologic subtypes of invasive breast carcinomas
Infiltrating ductal	76 %
Invasive lobular	8 %
Ductal/lobular	7 %
Mucinous (colloid)	2.4 %
Tubular	1.5 %
Medullary	1.2 %
Papillary	1 %
Other subtypes, including: ● Metaplastic breast cancer ● Invasive micropapillary breast cancer	less than 5 %

• Ductal carcinoma in situ (DCIS) is described as a proliferation of abnormal cells confined within the mammary ductal system.
• DCIS is commonly classified with respect to architectural and cytologic features as well as cell necrosis as follows:

• Low and intermediate grade (papillary, cribriform, and solid)
• High grade (comedo).

• DCIS signifies a herald to invasive breast cancer.

• The invasive breast carcinomas comprise numerous histologic subtypes.

• Infiltrating ductal carcinoma (the most common)
• Infiltrating lobular carcinoma (the second most common)

• Compared to the infiltrating ductal carcinomas, infiltrating lobular carcinomas are:

• Generally multicentric or may be bilateral
• Usually more differentiated
• Hormone receptor-positive
• May arise in older women
• As a role they metastasize later but if metastasize,
• Sometimes spread to unusual locations, such as:

• The meninges
• The peritoneum
• The gastrointestinal tract

Diagram showing localized and invasive lobular carcinoma in situ (LCIS).https://en.wikipedia.org/wiki/Lobular_carcinoma_in_situ

Gross Pathology

• On gross pathology, a discrete mass within the breast tissue that infiltrates stroma and or surrounding adipose tissue, creating a stellate, scar-like appearance (scirrhous carcinoma) is characteristic of Invasive ductal carcinoma (the most common type of invasive breast cancer).
• Important: The gross appearance of invasive ductal carcinoma might be similar to the fat necrosis.
• The following is a comprehensive description of probable gross findings:
  • Firm, poorly circumscribed, contracts from surrounding tissue, hard cartilaginous consistency, grating sound when scraped, streaks of chalky white elastotic stroma penetrating surrounding stroma ("crab like"), calcification
  • Large tumors have hemorrhage, necrosis and cystic degeneration
  • May be fixed to chest wall and cause skin dimpling or nipple retraction
    
• Shown below is a typical gross appearance of the breast cancer: a pale area in the yellow texture of the normal breast.

Typical macroscopic (gross) appearance of the cut surface of a mastectomy specimen containing cancer, in this case, invasive ductal carcinoma of the breast, pale area at the center. Source: Wikipedia

Microscopic Pathology

• On microscopic histopathological analysis, Mitotic figures, and pleomorphism are characteristic findings of high-grade breast cancers.
• The following is the microscopic description of breast tumors:

• Sheets, nests, cords or individual cells
• Tubular formations are prominent in well-differentiated tumors but absent in poorly differentiated tumors
• Tumor cells are more pleomorphic than lobular carcinoma
• Stroma usually desmoplastic and may obscure tumor cells
• Calcification in 60% of cases, variable necrosis
• Elastosis involves wall of vessels and ducts and causes grossly noted chalky streaks
• Often DCIS (up to 80%), perineural invasion (28%)
• Mitotic figures are often prominent
• Mast cells are associated with low-grade tumors
• Uncommon features: eosinophils (BMC Cancer 2007;7:165), intraluminal crystalloids (Arch Pathol Lab Med 1997;121:593)
• No myoepithelial cell lining (as seen in DCIS or benign lesions)

• Angiolymphatic invasion:

• In 35% - differs from tissue retraction because:
• Occurs outside margin of carcinoma
• Does do not conform precisely to space it is in
• The endothelial lining is present and is CD31+, Factor VIII+
• Blood vessels are in the vicinity

• Shown below are micrographs of breast cancer.

Her2 gene amplification by FISH (fluorescent in situ hybridization) in breast cancer cells. Case courtesy of Irina Pav. ttps://commons.wikimedia.org/wiki/File:FISH_Her2.jpg

HER2 FISH on Breast Cancer. Case courtesy of Anista lista. https://commons.wikimedia.org/wiki/File:HER2_FISH.jpg

Breast cancer: Lobular carcinoma in situ (LCIS), H&E, 20x. Case courtesy of Difu Wu. https://commons.wikimedia.org/wiki/File:Lobular_carcinoma_in_situ.jpg

Micrograph showing a lymph node invaded by ductal breast carcinoma and with extranodal extension of tumour.The dark purple (center) is lymphocytes (part of a normal lymph node). Surrounding the lymphocytes and extending into the surrounding fat (top of image) is ductal breast carcinoma. H&E stain. https://commons.wikimedia.org/wiki/File:Breast_carcinoma_in_a_lymph_node.jpg

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Genetics

• Breast cancer, like other cancers, occurs because of an interaction between the environment and a defective gene.

• Normal cells divide as many times as needed and stop; they attach to other cells and stay in place in tissues.
• Cells become cancerous when mutations destroy their ability to stop dividing, to attach to other cells, and to stay where they belong.

• Normal cells will commit cell suicide (apoptosis) when they are no longer needed.
• Until then, they are protected from cell suicide by several protein clusters and pathways.
• One of the protective pathways is the PI3K/AKT pathway; another one is the RAS/MEK/ERK pathway. *Sometimes the genes along these protective pathways are mutated in a way that turns them permanently "on", rendering the cell incapable of committing suicide when it is no longer needed. This is one of the steps that cause cancer in combination with other mutations.
• Normally, the PTEN protein turns off the PI3K/AKT pathway when the cell is ready for cell suicide.
• In some breast cancers, the gene for the PTEN protein is mutated, so the PI3K/AKT pathway is stuck in the "on" position, and the cancer cell does not commit suicide.
• Mutations that can lead to breast cancer have been experimentally linked to estrogen exposure and failure of immune surveillance, the removal of malignant cells throughout one's life by the immune system.
• Abnormal growth factor signaling in the interaction between stromal cells and epithelial cells can facilitate malignant cell growth. In breast adipose tissue, overexpression of leptin leads to increased cell proliferation and cancer.
• In the United States, 10 to 20 % of patients with breast cancer or ovarian cancer have a first- or second-degree relative with one of these diseases.
• The familial tendency to develop these cancers is called hereditary breast—ovarian cancer syndrome.
• The best known of these, the BRCA mutations, confer a lifetime risk of breast cancer of between 60 and 85 % and a lifetime risk of ovarian cancer of between 15 and 40 %.
• Some mutations associated with cancer, such as p53, BRCA1 and BRCA2, occur in mechanisms to correct errors in DNA.
• These mutations are either inherited or acquired after birth. Presumably, they allow further mutations, which lead to uncontrolled division, lack of attachment, and metastasis to distant organs.
• However, there is strong evidence of residual risk variation that goes well beyond hereditary BRCA gene mutations between carrier families; this is caused by unobserved risk factors.
• It implicates that environmental factors and other causes are triggers for breast cancer.
• The inherited mutation in BRCA1 or BRCA2 genes can interfere with repair of DNA cross links and DNA double strand breaks (known functions of the encoded protein).
• Because of this repair deficit, risks from carcinogenic chemicals and ionizing radiation can increase.
• These carcinogens cause DNA damage, such as to DNA cross links and double strand breaks that often require repairs by pathways containing BRCA1 and BRCA2.
• But it is these repair pathways that can be crippled by inherited mutation.
• There is evidence that cancer risks increase in mutation carriers exposed to such opportunistic carcinogens.
• Thus, risks for cancers may be reduced by avoiding or compensating for carcinogens that exploit the inherited BRCA gene deficiency
• However, mutations in BRCA genes account for only 2 to 3 % of all breast cancers.
• About half of hereditary breast–ovarian cancer syndromes involve unknown genes.

• Today, breast cancer, like other forms of cancer, is considered to be the final outcome of multiple environmental and hereditary factors. Some of the effects of environmental and hereditary factors that ultimately cause breast cancer are:

1. Lesions to DNA such as genetic mutations. Exposure to estrogen has been experimentally linked to the mutations that cause breast cancer. Beyond the contribution of estrogen, research has implicated viral oncogenesis and the contribution of ionizing radiation.
2. Failure of immune surveillance, which usually removes malignancies at early phases of their natural history.
3. Abnormal growth factor signaling in the interaction between stromal cells and epithelial cells. For example: in the angiogenesis, it is necessary to promote new blood vessel growth near new cancers.
4. Inherited defects in DNA repair genes, such as BRCA1, BRCA2 and p53.

• The followings are genes that might be associated with an increased risk for breast cancer. Nevertheless, the risk associated with these genes is not well understood yet.

• CHEK2
• BRIP1
• ATM
• PALB2

8RAD51

• BARD1

8MRE11A

• 8NBN
• RAD50

• In the'Associated conditions below, you will find the known hereditary syndromes with an increased risk of breast cancer.

Associated Conditions

• Hereditary Breast and Ovarian Cancer (HBOC) Syndrome: mutations in the BRCA1 or BRCA2 gene
• Cowden syndrome: mutations in the PTEN gene
• Li Fraumeni syndrome: mutations in the TP53 gene
• Hereditary Diffuse Gastric Cancer: mutations in the CDH1 gene
• Peutz-Jeghers syndrome: mutations in the STK11 gene

Bone Metastasis

• Bone is the most common site of breast cancer distant spread. Bone metastases due to breast cancer cause major morbidity, decrease survival and reduce quality of life of many patients.

Cancer influence on the skeleton results in two main negative consequences: pain and Skeletal-Related events (SREs), defined as any of the following:

• Pathologic fracture,
• A requirement for surgical intervention and palliative radiotherapy to bone lesions,
• spinal cord compression,
• hypercalcemia of malignancy .

In fact, SREs constitute readily measured clinical parameters that are employed in clinics and clinical trials.

• Many disciplines should be involved in the management of breast cancer bone metastases, including medical oncology, pain and palliative care, radiation oncology, orthopedic surgery and neurosurgery. Systemic therapy delays the progression of bone metastases and provides palliation; it includes endocrine therapy, biologic agents, chemotherapy, bisphosphonate therapy and the new osteoclast inhibitors.
• A thorough knowledge of the molecular basis of bone metastasis caused by breast cancer is essential for the understanding of the therapeutic approach. In fact, The normal balance between bone resorption and deposition is significantly affected by cancer. Bone metastases due to breast cancer are mostly osteolytic lesions, though predominant osteoblastic disease can occur .

The breast cancer cells and the bone microenvironment interact extensively through many chemical mediators resulting in bone destruction and tumor growth. These molecular mediators (pimarily Osteopontin, CXCR4, CTGF and Interleukin-11) exert their effect on osteoclasts which in turn cause bone resorption. This osteoclast-mediated bone resorption is thought to be the product of the action of numerous molecules including:

• PTHrP (Parathyroid Hormone–related Peptide),
• Tumor Necrosis Factor α (TNF-α),
• Cytokines such as Interleukin-1, Interleukin-6, Interleukin-8, and interleukin-11

• These factors signal osteoblasts (the bone-building cells) to induce osteoclast differentiation through the RANKL (the ligand for the receptor activator of nuclearfactor-κB [RANK])- RANK signaling. When Osteoclasts lyse bone, they cause the release of growth factors such as bone morphogenetic proteins (BMPs), IGF-I and TGF-β from the bone matrix which stimulate and maintain tumor cell proliferation and induce further release of PTHrP .

Pathophysiology of bone metastasis in breast cancer. The diagram is the authors' (Soroush Seifirad) own work.