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== Pathophysiology == {{See also|Carcinogenesis}} [[File:Lobules and ducts of the breast.jpg|thumb|[[Lactiferous duct|Ducts]] and lobules are the main locations of breast cancers.]] [[File:Signal transduction pathways.svg|thumb|Overview of signal transduction pathways involved in [[apoptosis|programmed cell death]]. Mutations leading to loss of this ability can lead to cancer formation.]] The major causes of sporadic breast cancer are associated with hormone levels. Breast cancer is promoted by estrogen. This hormone activates the development of breast throughout puberty, menstrual cycles and pregnancy. The imbalance between estrogen and progesterone during the menstrual phases causes cell proliferation. Moreover, [[4-Hydroxyestrone|oxidative metabolites of estrogen]] can increase DNA damage and mutations. Repeated cycling and the impairment of repair process can transform a normal cell into pre-malignant and eventually malignant cell through mutation. During the [[pre-malignant]] stage, high proliferation of [[stromal cell]]s can be activated by estrogen to support the development of breast cancer. During the ligand binding activation, the ER can regulate gene expression by interacting with estrogen response elements within the promotor of specific genes. The expression and activation of ER due to lack of estrogen can be stimulated by extracellular signals.<ref>{{cite journal | vauthors = Williams C, Lin CY | title = Oestrogen receptors in breast cancer: basic mechanisms and clinical implications | journal = ecancermedicalscience | volume = 7 | pages = 370 | date = November 2013 | pmid = 24222786 | pmc = 3816846 | doi = 10.3332/ecancer.2013.370 }}</ref> The ER directly binding with the several proteins, including growth factor receptors, can promote the expression of genes related to cell growth and survival.<ref>{{cite journal | vauthors = Levin ER, Pietras RJ | title = Estrogen receptors outside the nucleus in breast cancer | journal = Breast Cancer Research and Treatment | volume = 108 | issue = 3 | pages = 351β361 | date = April 2008 | pmid = 17592774 | doi = 10.1007/s10549-007-9618-4 }}</ref> Breast cancer, like other [[cancer]]s, occurs because of an interaction between an environmental (external) factor and a genetically susceptible host. 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 they lose their ability to stop dividing, to attach to other cells, to stay where they belong, and to die at the proper time. Normal cells will self-destruct ([[apoptosis|programmed cell death]]) when they are no longer needed. Until then, cells are protected from programmed death 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 self-destructing 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 programmed cell death. 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 self-destruct.<ref>{{cite conference | vauthors = Lee A, Arteaga C |title = 32nd Annual CTRC-AACR San Antonio Breast Cancer Symposium |book-title = Sunday Morning Year-End Review |date = 14 December 2009 |url = http://www.sabcs.org/Newsletter/Docs/SABCS_2009_Issue5.pdf |archive-url = https://web.archive.org/web/20130813021816/http://www.sabcs.org/Newsletter/Docs/SABCS_2009_Issue5.pdf |archive-date = 13 August 2013 }}</ref> Mutations that can lead to breast cancer have been experimentally linked to estrogen exposure.<ref name="pmid16675129">{{cite journal | vauthors = Cavalieri E, Chakravarti D, Guttenplan J, Hart E, Ingle J, Jankowiak R, Muti P, Rogan E, Russo J, Santen R, Sutter T | title = Catechol estrogen quinones as initiators of breast and other human cancers: implications for biomarkers of susceptibility and cancer prevention | journal = Biochimica et Biophysica Acta (BBA) - Reviews on Cancer| volume = 1766 | issue = 1 | pages = 63β78 | date = August 2006 | pmid = 16675129 | doi = 10.1016/j.bbcan.2006.03.001 }}</ref> Additionally, G-protein coupled [[estrogen receptor]]s have been associated with various cancers of the female reproductive system including breast cancer.<ref>{{cite journal | vauthors = Filardo EJ | title = A role for G-protein coupled estrogen receptor (GPER) in estrogen-induced carcinogenesis: Dysregulated glandular homeostasis, survival and metastasis | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 176 | pages = 38β48 | date = February 2018 | pmid = 28595943 | doi = 10.1016/j.jsbmb.2017.05.005 }}</ref> Abnormal [[growth factor]] signaling in the interaction between [[stromal cell]]s and [[epithelial cell]]s can facilitate malignant cell growth.<ref name="pmid12817994">{{cite journal | vauthors = Haslam SZ, Woodward TL | title = Host microenvironment in breast cancer development: epithelial-cell-stromal-cell interactions and steroid hormone action in normal and cancerous mammary gland | journal = Breast Cancer Research | volume = 5 | issue = 4 | pages = 208β15 | date = June 2003 | pmid = 12817994 | pmc = 165024 | doi = 10.1186/bcr615 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Wiseman BS, Werb Z | title = Stromal effects on mammary gland development and breast cancer | journal = Science | volume = 296 | issue = 5570 | pages = 1046β9 | date = May 2002 | pmid = 12004111 | pmc = 2788989 | doi = 10.1126/science.1067431 | bibcode = 2002Sci...296.1046W }}</ref> In breast adipose tissue, overexpression of leptin leads to increased cell proliferation and cancer.<ref name="pmid20889333">{{cite journal | vauthors = JardΓ© T, Perrier S, Vasson MP, Caldefie-ChΓ©zet F | title = Molecular mechanisms of leptin and adiponectin in breast cancer | journal = European Journal of Cancer | volume = 47 | issue = 1 | pages = 33β43 | date = January 2011 | pmid = 20889333 | doi = 10.1016/j.ejca.2010.09.005 }}</ref> Some mutations associated with cancer, such as [[p53]], ''[[BRCA1]]'' and ''[[BRCA2]]'', occur in mechanisms to correct errors in [[DNA]]. The inherited mutation in ''BRCA1'' or ''BRCA2'' genes can interfere with repair of [[Crosslinking of DNA|DNA crosslinks]] and [[double-strand breaks]] (known functions of the encoded protein).<ref>{{cite journal | vauthors = Patel KJ, Yu VP, Lee H, Corcoran A, Thistlethwaite FC, Evans MJ, Colledge WH, Friedman LS, Ponder BA, Venkitaraman AR | title = Involvement of Brca2 in DNA repair | journal = Molecular Cell | volume = 1 | issue = 3 | pages = 347β57 | date = February 1998 | pmid = 9660919 | doi = 10.1016/S1097-2765(00)80035-0 | doi-access = free }}</ref> These carcinogens cause DNA damage such as DNA crosslinks and double-strand breaks that often require repairs by pathways containing ''BRCA1'' and ''BRCA2''.<ref>{{cite journal | vauthors = Marietta C, Thompson LH, Lamerdin JE, Brooks PJ | title = Acetaldehyde stimulates FANCD2 monoubiquitination, H2AX phosphorylation, and BRCA1 phosphorylation in human cells in vitro: implications for alcohol-related carcinogenesis | journal = Mutation Research | volume = 664 | issue = 1β2 | pages = 77β83 | date = May 2009 | pmid = 19428384 | pmc = 2807731 | doi = 10.1016/j.mrfmmm.2009.03.011 | bibcode = 2009MRFMM.664...77M }}</ref><ref>{{cite journal | vauthors = Theruvathu JA, Jaruga P, Nath RG, Dizdaroglu M, Brooks PJ | title = Polyamines stimulate the formation of mutagenic 1,N2-propanodeoxyguanosine adducts from acetaldehyde | journal = Nucleic Acids Research | volume = 33 | issue = 11 | pages = 3513β20 | year = 2005 | pmid = 15972793 | pmc = 1156964 | doi = 10.1093/nar/gki661 }}</ref> [[GATA-3]] directly controls the expression of estrogen receptor (ER) and other genes associated with epithelial differentiation, and the loss of GATA-3 leads to loss of differentiation and poor prognosis due to cancer cell invasion and metastasis.<ref>{{cite journal | vauthors = Kouros-Mehr H, Kim JW, Bechis SK, Werb Z | title = GATA-3 and the regulation of the mammary luminal cell fate | journal = Current Opinion in Cell Biology | volume = 20 | issue = 2 | pages = 164β70 | date = April 2008 | pmid = 18358709 | pmc = 2397451 | doi = 10.1016/j.ceb.2008.02.003 }}</ref>
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