Breast cancer pathophysiology: Difference between revisions
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==Pathophysiology== | ==Pathophysiology== | ||
Today, breast cancer, like other forms of cancer, is considered to be the final outcome of multiple environmental and hereditary factors. | Today, breast cancer, like other forms of cancer, is considered to be the final outcome of multiple environmental and hereditary factors. | ||
# Lesions to [[DNA]] such as [[genetic mutations]]. Exposure to estrogen has been experimentally linked to the mutations that cause breast cancer.<ref name="pmid16675129">{{cite journal |author=Cavalieri E, Chakravarti D, Guttenplan J, ''et al'' |title=Catechol estrogen quinones as initiators of breast and other human cancers: implications for biomarkers of susceptibility and cancer prevention |journal=Biochim. Biophys. Acta |volume=1766 |issue=1 |pages=63-78 |year=2006 |pmid=16675129 |doi=10.1016/j.bbcan.2006.03.001}}</ref> Beyond the contribution of estrogen, research has implicated viral oncogenesis and the contribution of [[ionizing radiation]]. | # Lesions to [[DNA]] such as [[genetic mutations]]. Exposure to estrogen has been experimentally linked to the mutations that cause breast cancer.<ref name="pmid16675129">{{cite journal |author=Cavalieri E, Chakravarti D, Guttenplan J, ''et al'' |title=Catechol estrogen quinones as initiators of breast and other human cancers: implications for biomarkers of susceptibility and cancer prevention |journal=Biochim. Biophys. Acta |volume=1766 |issue=1 |pages=63-78 |year=2006 |pmid=16675129 |doi=10.1016/j.bbcan.2006.03.001}}</ref> Beyond the contribution of estrogen, research has implicated viral oncogenesis and the contribution of [[ionizing radiation]]. | ||
# Failure of immune surveillance, which usually removes malignancies at early phases of their natural history. | # Failure of immune surveillance, which usually removes malignancies at early phases of their natural history. | ||
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[[Image:Breast cancer.png]] | [[Image:Breast cancer.png]] | ||
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 | 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 is the [[Ras (protein)|RAS]]/[[Mitogen-activated protein kinase kinase|MEK]]/[[Extracellular signal-regulated kinases|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 causes cancer in combination with other mutations. Normally, the [[PTEN (gene)|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.<ref>{{Cite conference | 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 (protein)|RAS]]/[[Mitogen-activated protein kinase kinase|MEK]]/[[Extracellular signal-regulated kinases|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 causes cancer in combination with other mutations. Normally, the [[PTEN (gene)|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.<ref>{{Cite conference | ||
| coauthors = Adrian Lee, Carlos Arteaga | | coauthors = Adrian Lee, Carlos Arteaga | ||
| title = 32nd Annual CTRC-AACR San Antonio Breast Cancer Symposium | | title = 32nd Annual CTRC-AACR San Antonio Breast Cancer Symposium | ||
Revision as of 03:54, 20 July 2015
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
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Breast Cancer Microchapters |
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Diagnosis |
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Treatment |
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Case Studies |
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Breast cancer pathophysiology On the Web |
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American Roentgen Ray Society Images of Breast cancer pathophysiology |
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Risk calculators and risk factors for Breast cancer pathophysiology |
Overview
Pathophysiology
Today, breast cancer, like other forms of cancer, is considered to be the final outcome of multiple environmental and hereditary factors.
- Lesions to DNA such as genetic mutations. Exposure to estrogen has been experimentally linked to the mutations that cause breast cancer.[1] Beyond the contribution of estrogen, research has implicated viral oncogenesis and the contribution of ionizing radiation.
- Failure of immune surveillance, which usually removes malignancies at early phases of their natural history.
- Abnormal growth factor signaling in the interaction between stromal cells and epithelial cells, for example in the angiogenesis necessary to promote new blood vessel growth near new cancers.
- Inherited defects in DNA repair genes, such as BRCA1, BRCA2 and p53.
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 causes 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.[2]
Mutations that can lead to breast cancer have been experimentally linked to estrogen exposure.[1]
Failure of immune surveillance, the removal of malignant cells throughout one's life by the immune system.[3] Abnormal growth factor signaling in the interaction between stromal cells and epithelial cells can facilitate malignant cell growth.[4][5] In breast adipose tissue, overexpression of leptin leads to increased cell proliferation and cancer.[6]
In the United States, 10 to 20 percent of patients with breast cancer and patients with 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 percent and a lifetime risk of ovarian cancer of between 15 and 40 percent. 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 allow uncontrolled division, lack of attachment, and metastasis to distant organs.[7][8]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.[9] This implicates environmental and other causes as triggers for breast cancers. 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)[10] Because of this repair deficit, risks from carcinogenic chemicals and ionizing radiation can increase[11]These carcinogens cause DNA damage such as DNA cross links and double strand breaks that often require repairs by pathways containing BRCA1 and BRCA2.[12][13] 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.[14] Thus risks for cancers may be reduced by avoiding or compensating for carcinogens that exploit the inherited BRCA gene deficiency[15] However, mutations in BRCA genes account for only 2 to 3 percent of all breast cancers.[16] About half of hereditary breast–ovarian cancer syndromes involve unknown genes.
Microscopic Pathology
Shown below is a micrograph of high grade invasive ductal carcinoma showing minimal tubule formation,marked pleomorphism and numerous mitotic figures.
Metastasis
Most people understand breast cancer as something that happens in the breast. However it can metastasise (spread) via lymphatics to nearby lymph nodes, usually those under the arm. That is why surgery for breast cancer always involves some type of surgery for the glands under the arm — either axillary clearance, sampling, or sentinel node biopsy.
Breast cancer can also spread to other parts of the body via blood vessels. So it can spread to the lungs, pleura (the lining of the lungs), liver, brain, and most commonly to the bones. Seventy percent of the time that breast cancer spreads to other locations, it spreads to bone, especially the vertebrae and the long bones of the arms, legs, and ribs. Breast cancer cells "set up house" in the bones and form tumors. Usually when breast cancer spreads to bone, it eats away healthy bone, causing weak spots, where the bones can break easily. That is why breast cancer patients are often seen wearing braces or using a wheelchair, and why they complain about aching bones.
When breast cancer is found in bones, it has usually spread to more than one site. At this stage, it is treatable, often for many years, but it is not curable. Like normal breast cells, these tumors in the bone often thrive on female hormones, especially estrogen. Therefore, the doctor often treats the patient with medicines that lower her estrogen levels.
Video
{{#ev:youtube|chA-plXrPzI}}
References
- ↑ 1.0 1.1 Cavalieri E, Chakravarti D, Guttenplan J; et al. (2006). "Catechol estrogen quinones as initiators of breast and other human cancers: implications for biomarkers of susceptibility and cancer prevention". Biochim. Biophys. Acta. 1766 (1): 63–78. doi:10.1016/j.bbcan.2006.03.001. PMID 16675129.
- ↑ "32nd Annual CTRC-AACR San Antonio Breast Cancer Symposium" (PDF). Sunday Morning Year-End Review. Dec. 14, 2009. Unknown parameter
|coauthors=ignored (help); Check date values in:|date=(help) - ↑ Farlex (2005). "Immunological Surveilliance". The Free Dictionary. Retrieved 2008-02-10.
- ↑ Haslam SZ, Woodward TL (2003). "Host microenvironment in breast cancer development: epithelial-cell-stromal-cell interactions and steroid hormone action in normal and cancerous mammary gland". Breast Cancer Res. 5 (4): 208–15. doi:10.1186/bcr615. PMC 165024. PMID 12817994. Unknown parameter
|month=ignored (help) - ↑ Wiseman BS, Werb Z (2002). "Stromal effects on mammary gland development and breast cancer". Science. 296 (5570): 1046–9. doi:10.1126/science.1067431. PMC 2788989. PMID 12004111. Unknown parameter
|month=ignored (help) - ↑ Jardé T, Perrier S, Vasson MP, Caldefie-Chézet F (2011). "Molecular mechanisms of leptin and adiponectin in breast cancer". Eur. J. Cancer. 47 (1): 33–43. doi:10.1016/j.ejca.2010.09.005. PMID 20889333. Unknown parameter
|month=ignored (help) - ↑ American Cancer Society (2005). "Breast Cancer Facts & Figures 2005–2006" (PDF). Archived from the original (PDF) on June 13, 2007. Retrieved 2007-04-26.
- ↑ Dunning AM, Healey CS, Pharoah PD, Teare MD, Ponder BA, Easton DF (1999). "A systematic review of genetic polymorphisms and breast cancer risk". Cancer Epidemiology, Biomarkers & Prevention. 8 (10): 843–54. PMID 10548311. Unknown parameter
|month=ignored (help) - ↑ Begg CB, Haile RW, Borg A; et al. (2008). "Variation of breast cancer risk among BRCA1/2 carriers". JAMA. 299 (2): 194–201. doi:10.1001/jama.2007.55-a. PMC 2714486. PMID 18182601. Unknown parameter
|month=ignored (help) - ↑ Patel KJ, Yu VP, Lee H; et al. (1998). "Involvement of Brca2 in DNA repair". Mol. Cell. 1 (3): 347–57. doi:10.1016/S1097-2765(00)80035-0. PMID 9660919. Unknown parameter
|month=ignored (help) - ↑ Friedenson B (2000). "Is mammography indicated for women with defective BRCA genes? Implications of recent scientific advances for the diagnosis, treatment, and prevention of hereditary breast cancer". MedGenMed. 2 (1): E9. PMID 11104455. Unknown parameter
|month=ignored (help) - ↑ Marietta C, Thompson LH, Lamerdin JE, Brooks PJ (2009). "Acetaldehyde stimulates FANCD2 monoubiquitination, H2AX phosphorylation, and BRCA1 phosphorylation in human cells in vitro: implications for alcohol-related carcinogenesis". Mutat. Res. 664 (1–2): 77–83. doi:10.1016/j.mrfmmm.2009.03.011. PMC 2807731. PMID 19428384. Unknown parameter
|month=ignored (help) - ↑ Theruvathu JA, Jaruga P, Nath RG, Dizdaroglu M, Brooks PJ (2005). "Polyamines stimulate the formation of mutagenic 1,N2-propanodeoxyguanosine adducts from acetaldehyde". Nucleic Acids Res. 33 (11): 3513–20. doi:10.1093/nar/gki661. PMC 1156964. PMID 15972793.
- ↑ Friedenson B (2012). "Preventing hereditary cancers caused by opportunistic carcinogens". J Med Med Sci. 3: 160–178.
- ↑ Friedenson B, “Preventing hereditary cancers associated with BRCA1 and BRCA2 gene mutations” 2012
- ↑ Wooster R, Weber BL (2003). "Breast and ovarian cancer". N. Engl. J. Med. 348 (23): 2339–47. doi:10.1056/NEJMra012284. PMID 12788999. Unknown parameter
|month=ignored (help)