Array ( [0] => {{short description|Gene known for its role in breast cancer}} [1] => {{cs1 config|name-list-style=vanc}} [2] => {{Infobox_gene}} [3] => '''Breast cancer type 1 susceptibility protein''' is a [[protein]] that in humans is encoded by the '''''BRCA1''''' ({{IPAc-en|ˌ|b|r|æ|k|ə|ˈ|w|ʌ|n}}) [[gene]].{{cite web | url = http://www.healthcentral.com/breast-cancer/c/78/9925/brca1-brca2 | vauthors = Hamel PJ | title = BRCA1 and BRCA2: No Longer the Only Troublesome Genes Out There | publisher = HealthCentral | date = 2007-05-29 | access-date = 2010-07-02}} [[Ortholog]]s are common in other [[vertebrate]] species, whereas [[invertebrate]] genomes may encode a more distantly related gene.{{cite web |title=BRCA1 gene tree |url=http://www.ensembl.org/Multi/GeneTree/Image?gt=ENSGT00440000034289 |publisher=Ensembl}} ''BRCA1'' is a human [[tumor suppressor gene]]{{cite journal | vauthors = Duncan JA, Reeves JR, Cooke TG | title = BRCA1 and BRCA2 proteins: roles in health and disease | journal = Molecular Pathology | volume = 51 | issue = 5 | pages = 237–47 | date = October 1998 | pmid = 10193517 | pmc = 395646 | doi = 10.1136/mp.51.5.237 }}{{cite journal | vauthors = Yoshida K, Miki Y | title = Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage | journal = Cancer Science | volume = 95 | issue = 11 | pages = 866–71 | date = November 2004 | pmid = 15546503 | doi = 10.1111/j.1349-7006.2004.tb02195.x | s2cid = 24297965 | doi-access = free }} (also known as a [[caretaker gene]]) and is responsible for repairing [[DNA]].{{cite web | url = http://www.cap.org/apps/cap.portal?_nfpb=true&cntvwrPtlt_actionOverride=%2Fportlets%2FcontentViewer%2Fshow&_windowLabel=cntvwrPtlt&cntvwrPtlt{actionForm.contentReference}=cap_today%2Ffeature_stories%2F0906BRCA.html&_state=maximized&_pageLabel=cntvwr | title = BRCA: What we know now | vauthors = Check W | publisher = College of American Pathologists | date = September 2006 | access-date = 2010-08-23}} [4] => [5] => ''BRCA1'' and ''[[BRCA2]]'' are unrelated proteins,{{cite journal | vauthors = Irminger-Finger I, Ratajska M, Pilyugin M | title = New concepts on BARD1: Regulator of BRCA pathways and beyond | journal = The International Journal of Biochemistry & Cell Biology | volume = 72 | pages = 1–17 | year = 2016 | pmid = 26738429 | doi = 10.1016/j.biocel.2015.12.008 | doi-access = free }} but both are normally expressed in the cells of [[breast]] and other tissue, where they help [[DNA repair|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 [[Double-strand break repair model|repair of DNA double-strand breaks]].{{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 | doi-access = free }}{{cite web | url = http://www.scivee.tv/node/6090 | title = Breast cancer genes protect against some leukemias and lymphomas | vauthors = Friedenson B | date = 2008-06-08 | format = video | publisher = SciVee }} 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]].{{cite web | url = http://www.pamf.org/health/guidelines/geneticscreening.html | title = Breast and Ovarian Cancer Genetic Screening | publisher = Palo Alto Medical Foundation | access-date = 2008-10-11| archive-url= https://web.archive.org/web/20081004080235/http://www.pamf.org/health/guidelines/geneticscreening.html| archive-date= 4 October 2008 | url-status= live}}{{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 | doi-access = free }} ''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.{{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 | date = April 2010 | pmid = 20400477 | doi = 10.1093/carcin/bgq069 | doi-access = free }} [6] => [7] => ''BRCA1'' combines with other tumor suppressors, DNA damage sensors and [[Signal transduction|signal transducers]] to form a large multi-subunit protein complex known as the ''BRCA1''-associated genome surveillance complex (BASC). The ''BRCA1'' protein associates with [[RNA polymerase II]], and through the [[C-terminus|C-terminal]] domain, also interacts with [[histone deacetylase]] complexes. Thus, this protein plays a role in transcription, and [[DNA repair]] of double-strand DNA breaks [[ubiquitin]]ation, [[transcriptional regulation]] as well as other functions.{{cite journal | vauthors = Starita LM, Parvin JD | title = The multiple nuclear functions of BRCA1: transcription, ubiquitination and DNA repair | journal = Current Opinion in Cell Biology | volume = 15 | issue = 3 | pages = 345–350 | year = 2003 | pmid = 12787778 | doi = 10.1016/S0955-0674(03)00042-5 }} [8] => [9] => Methods to test for the likelihood of a patient with mutations in ''BRCA1'' and ''BRCA2'' developing cancer were covered by [[Biological patent|patents]] owned or controlled by [[Myriad Genetics]]. Myriad's business model of offering the diagnostic test exclusively led from Myriad being a startup in 1994 to being a publicly traded company with 1200 employees and about $500 million in annual revenue in 2012;[http://investor.myriad.com/index.cfm Myriad Investor Page—see "Myriad at a glance"] {{Webarchive|url=https://web.archive.org/web/20121018224334/http://investor.myriad.com/index.cfm |date=2012-10-18 }} accessed October 2012 it also led to controversy over high prices and the inability to obtain second opinions from other diagnostic labs, which in turn led to the landmark ''[[Association for Molecular Pathology v. Myriad Genetics]]'' lawsuit.{{cite web |url= https://www.nytimes.com/2009/05/13/health/13patent.html |title= Cancer Patients Challenge the Patenting of a Gene | vauthors = Schwartz J |date= 2009-05-12 |id= Health |work=The New York Times}} [10] => [11] => ==Discovery== [12] => The first evidence for the existence of a gene encoding a DNA repair enzyme involved in breast cancer susceptibility was provided by [[Mary-Claire King]]'s laboratory at [[University of California, Berkeley|UC Berkeley]] in 1990.{{cite journal | vauthors = Hall JM, Lee MK, Newman B, Morrow JE, Anderson LA, Huey B, King MC | title = Linkage of early-onset familial breast cancer to chromosome 17q21 | journal = Science | volume = 250 | issue = 4988 | pages = 1684–9 | date = December 1990 | pmid = 2270482 | doi = 10.1126/science.2270482 | bibcode = 1990Sci...250.1684H }} Four years later, after an international race to find it,[http://scienceblog.cancerresearchuk.org/2012/02/28/high-impact-science-tracking-down-the-brca-genes-part-1/ High-Impact Science: Tracking down the BRCA genes (Part 1)] {{Webarchive|url=https://web.archive.org/web/20160220074818/http://scienceblog.cancerresearchuk.org/2012/02/28/high-impact-science-tracking-down-the-brca-genes-part-1/ |date=2016-02-20 }} – Cancer Research UK science blog, 2012 the gene was cloned in 1994 by scientists at University of Utah, National Institute of Environmental Health Sciences (NIEHS) and [[Myriad Genetics]].{{cite journal | vauthors = Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, Liu Q, Cochran C, Bennett LM, Ding W | title = A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1 | journal = Science | volume = 266 | issue = 5182 | pages = 66–71 | date = October 1994 | pmid = 7545954 | doi = 10.1126/science.7545954 | bibcode = 1994Sci...266...66M | doi-access = free }} [13] => [14] => ==Gene location== [15] => [16] => 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)].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)] ''BRCA1'' [[orthologs]] have been identified in most [[vertebrate]]s for which complete genome data are available. [17] => [18] => ==Protein structure== [19] => The BRCA1 [[protein]] contains the following domains:{{cite journal | vauthors = Paterson JW | title = BRCA1: a review of structure and putative functions | journal = Dis. Markers | volume = 13 | issue = 4 | pages = 261–74 | date = February 1998 | pmid = 9553742 | doi = 10.1155/1998/298530 | doi-access = free }} [20] => * Zinc finger, C3HC4 type ([[RING finger domain|RING finger]]) [21] => * BRCA1 C Terminus ([[BRCT domain|BRCT]]) domain [22] => This protein also contains [[nuclear localization signal]]s and [[nuclear export signal]] motifs.{{cite journal | vauthors = Henderson BR | title = Regulation of BRCA1, BRCA2 and BARD1 intracellular trafficking | journal = BioEssays | volume = 27 | issue = 9 | pages = 884–93 | date = September 2005 | pmid = 16108063 | doi = 10.1002/bies.20277 | s2cid = 10138907 }} [23] => [24] => The human [[BRCA1 protein]] consists of four major protein domains; the [[RING finger domain|Znf C3HC4- RING domain]], the BRCA1 serine domain and two [[BRCT domain|BRCT]] domains. These domains encode approximately 27% of BRCA1 protein. There are six known isoforms of BRCA1,{{UniProt Full|P38398|Breast cancer type 1 susceptibility protein}} with isoforms 1 and 2 comprising 1863 amino acids each.{{citation needed|date=January 2016}} [25] => [26] => BRCA1 is unrelated to [[BRCA2]], i.e. they are not [[Sequence homology|homologs]] or [[Paralogy|paralogs]]. [27] => [[File:BRCA1partB.png|thumb|upright=2|alt=text|Domain map of BRCA1; RING, serine containing domain (SCD), and BRCT domains are indicated. Horizontal black lines indicate protein-binding domains for the listed partners. Red circles mark phosphorylation sites.{{cite journal | vauthors = Clark SL, Rodriguez AM, Snyder RR, Hankins GD, Boehning D | title = Structure-Function Of The Tumor Suppressor BRCA1 | journal = Comput Struct Biotechnol J | volume = 1 | issue = 1 | pages = e201204005|date=April 2012 | pmid = 22737296 | pmc = 3380633 | doi = 10.5936/csbj.201204005 }}]] [28] => [29] => ===Zinc RING finger domain=== [30] => [31] => The RING [[RING finger domain|motif]], a [[Zn finger]] found in eukaryotic peptides, is 40–60 amino acids long and consists of eight conserved metal-binding residues, two quartets of [[cysteine]] or [[histidine]] residues that coordinate two zinc atoms.{{cite journal | vauthors = Brzovic PS, Rajagopal P, Hoyt DW, King MC, Klevit RE | title = Structure of a BRCA1-BARD1 heterodimeric RING-RING complex | journal = Nature Structural & Molecular Biology | volume = 8 | issue = 10 | pages = 833–7 | date = October 2001 | pmid = 11573085 | doi = 10.1038/nsb1001-833 | s2cid = 37617901 }} This motif contains a short anti-parallel [[beta-sheet]], two zinc-binding loops and a central [[alpha helix]] in a small domain. This RING domain interacts with associated proteins, including [[BARD1]], which also contains a RING motif, to form a heterodimer. The BRCA1 RING motif is flanked by alpha helices formed by residues 8–22 and 81–96 of the BRCA1 protein. It interacts with a homologous region in BARD1 also consisting of a RING finger flanked by two [[alpha-helices]] formed from residues 36–48 and 101–116. These four helices combine to form a [[heterodimerization]] interface and stabilize the BRCA1-BARD1 heterodimer complex. Additional stabilization is achieved by interactions between adjacent residues in the flanking region and hydrophobic interactions. The BARD1/BRCA1 interaction is disrupted by tumorigenic amino acid substitutions in BRCA1, implying that the formation of a stable complex between these proteins may be an essential aspect of BRCA1 tumor suppression. [32] => [33] => The RING domain is an important element of [[Ubiquitin ligase#Individual E3 ubiquitin ligases|ubiquitin E3 ligases]], which catalyze protein ubiquitination. [[Ubiquitin]] is a small regulatory protein found in all tissues that direct proteins to compartments within the cell. BRCA1 polypeptides, in particular, Lys-48-linked polyubiquitin chains are dispersed throughout the resting cell nucleus, but at the start of [[DNA replication]], they gather in restrained groups that also contain [[BRCA2]] and BARD1. BARD1 is thought to be involved in the recognition and binding of protein targets for ubiquitination.{{cite journal | vauthors = Baer R | title = With the ends in sight: images from the BRCA1 tumor suppressor | journal = Nature Structural & Molecular Biology | volume = 8 | issue = 10 | pages = 822–4 | date = October 2001 | pmid = 11573079 | doi = 10.1038/nsb1001-822 | s2cid = 20552445 }} It attaches to proteins and labels them for destruction. Ubiquitination occurs via the BRCA1 fusion protein and is abolished by zinc [[chelation]]. The enzyme activity of the fusion protein is dependent on the proper folding of the RING domain.{{citation needed|date=January 2016}} [34] => [35] => ===Serine cluster domain=== [36] => [37] => BRCA1 serine cluster domain (SCD) spans amino acids 1280–1524. A portion of the domain is located in exons 11–13. High rates of mutation occur in exons 11–13. Reported phosphorylation sites of BRCA1 are concentrated in the SCD, where they are phosphorylated by [[ataxia telangiectasia mutated|ATM/ATR kinases]] both [[in vitro]] and [[in vivo]]. ATM/ATR are kinases activated by [[DNA damage]]. Mutation of serine residues may affect localization of BRCA1 to sites of DNA damage and DNA damage response function. [38] => [39] => ===BRCT domains=== [40] => [41] => The dual repeat [[BRCT domain]] of the BRCA1 protein is an elongated structure approximately 70 Å long and 30–35 Å wide.{{cite journal | vauthors = Williams RS, Green R, Glover JN | title = Crystal structure of the BRCT repeat region from the breast cancer-associated protein BRCA1 | journal = Nature Structural & Molecular Biology | volume = 8 | issue = 10 | pages = 838–42 | date = October 2001 | pmid = 11573086 | doi = 10.1038/nsb1001-838 | s2cid = 19275284 }} The 85–95 amino acid domains in BRCT can be found as single modules or as multiple tandem repeats containing two domains.{{cite journal | vauthors = Huyton T, Bates PA, Zhang X, Sternberg MJ, Freemont PS | title = The BRCA1 C-terminal domain: structure and function | journal = Mutat. Res. | volume = 460 | issue = 3–4 | pages = 319–32 | date = August 2000 | pmid = 10946236 | doi = 10.1016/S0921-8777(00)00034-3 }} Both of these possibilities can occur in a single protein in a variety of different conformations. The C-terminal BRCT region of the BRCA1 protein is essential for repair of DNA, transcription regulation and tumor suppressor function.{{cite journal | vauthors = Joo WS, Jeffrey PD, Cantor SB, Finnin MS, Livingston DM, Pavletich NP | title = Structure of the 53BP1 BRCT region bound to p53 and its comparison to the Brca1 BRCT structure | journal = Genes Dev. | volume = 16 | issue = 5 | pages = 583–93 | date = March 2002 | pmid = 11877378 | pmc = 155350 | doi = 10.1101/gad.959202 }} In BRCA1 the dual [[tandem repeat]] BRCT domains are arranged in a head-to-tail-fashion in the three-dimensional structure, burying 1600 Å of hydrophobic, solvent-accessible surface area in the interface. These all contribute to the tightly packed knob-in-hole structure that comprises the interface. These homologous domains interact to control cellular responses to [[DNA damage]]. A [[missense mutation]] at the interface of these two proteins can perturb the [[cell cycle]], resulting a greater risk of developing cancer.{{citation needed|date=May 2019}} [42] => [43] => ==Function and mechanism== [44] => [45] => 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 (FA-S),{{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}} 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]].{{Cite web|url=http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/D/DNArepair.html#DSBs|title=Kimball's Biologh Pages|access-date=2010-02-25|archive-date=2018-02-12|archive-url=https://web.archive.org/web/20180212073520/http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/D/DNArepair.html#DSBs}} FA-S is almost always a lethal condition in utero; only a handful cases of biallelic BRCA1 mutations have been reported in literature despite the high carrier frequencies in the Ashkenazim, and none since 2013.{{cite journal | vauthors = Domchek SM, Tang J, Stopfer J, Lilli DR, Hamel N, Tischkowitz M, Monteiro AN, Messick TE, Powers J, Yonker A, Couch FJ, Goldgar DE, Davidson HR, Nathanson KL, Foulkes WD, Greenberg RA | display-authors = 6 | title = Biallelic deleterious BRCA1 mutations in a woman with early-onset ovarian cancer | journal = Cancer Discovery | volume = 3 | issue = 4 | pages = 399–405 | date = April 2013 | pmid = 23269703 | pmc = 3625496 | doi = 10.1158/2159-8290.CD-12-0421 }} [46] => [47] => In the nucleus of many types of normal cells, the BRCA1 protein interacts with [[RAD51]] during repair of DNA double-strand breaks.{{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 }} 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.{{Cite journal |last1=Roy |first1=Rohini |last2=Chun |first2=Jarin |last3=Powell |first3=Simon N. |date=January 2012 |title=BRCA1 and BRCA2: different roles in a common pathway of genome protection |journal=Nature Reviews Cancer |language=en |volume=12 |issue=1 |pages=68–78 |doi=10.1038/nrc3181 |issn=1474-175X |pmc=4972490 |pmid=22193408}} [48] => [49] => BRCA1 is also involved in another type of DNA repair, termed [[DNA mismatch repair|mismatch repair]]. BRCA1 interacts with the DNA mismatch repair protein [[MSH2]].{{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 | doi-access = free }} MSH2, [[MSH6]], [[Poly (ADP-ribose) polymerase|PARP]] and some other proteins involved in single-strand repair are reported to be elevated in BRCA1-deficient mammary tumors.{{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 = M111.013334-1-M111.013334-19 | date = July 2012 | pmid = 22366898 | pmc = 3394939 | doi = 10.1074/mcp.M111.013334 |doi-access=free }} [50] => [51] => 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.{{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 | s2cid = 22109822 }} BRCA1 interacts with VCP.{{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 }} BRCA1 also interacts with [[Myc|c-Myc]], and other proteins that are critical to maintain genome stability.{{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 | doi-access = free }} [52] => [53] => 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.{{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 | doi-access = free }} This may explain a role for BRCA1 to promote lower fidelity DNA repair by [[non-homologous end joining]] (NHEJ).{{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 | doi-access = free }} 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.{{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 }} [54] => [55] => [[Formaldehyde]] and [[acetaldehyde]] are common environmental sources of DNA cross links that often require repairs mediated by BRCA1 containing pathways.{{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 | doi-access = free }} [56] => [57] => 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 (leading to FA-S); 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]].{{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 }} [58] => [59] => ===Transcription=== [60] => [61] => BRCA1 was shown to co-purify with the human RNA Polymerase II holoenzyme in HeLa extracts, implying it is a component of the holoenzyme.{{cite journal | vauthors = Scully R, Anderson SF, Chao DM, Wei W, Ye L, Young RA, Livingston DM, Parvin JD | title = BRCA1 is a component of the RNA polymerase II holoenzyme | journal = Proceedings of the National Academy of Sciences | volume = 94 | issue = 11 | pages = 5605–10 | year = 1997 | pmid = 9159119 | pmc = 20825 | doi = 10.1073/pnas.94.11.5605 | bibcode = 1997PNAS...94.5605S | doi-access = free }} Later research, however, contradicted this assumption, instead showing that the predominant complex including BRCA1 in HeLa cells is a 2 megadalton complex containing SWI/SNF.{{cite journal | vauthors = Bochar DA, Wang L, Beniya H, Kinev A, Xue Y, Lane WS, Wang W, Kashanchi F, Shiekhattar R | title = BRCA1 Is Associated with a Human SWI/SNF-Related Complex Linking Chromatin Remodeling to Breast Cancer | journal = Cell | volume = 102 | issue = 2 | pages = 257–265 | year = 2000 | pmid = 10943845 | doi = 10.1016/S0092-8674(00)00030-1 | doi-access = free }} SWI/SNF is a chromatin remodeling complex. Artificial tethering of BRCA1 to chromatin was shown to decondense heterochromatin, though the SWI/SNF interacting domain was not necessary for this role. BRCA1 interacts with the NELF-B ([[Cofactor of BRCA1|COBRA1]]) subunit of the [[Negative elongation factor|NELF]] complex. [62] => [63] => ==Mutations and cancer risk== [64] => [[File:BRCA1 and BRCA2 mutations and absolute cancer risk.jpg|thumb|310px|Absolute risk of cancers in BRCA1 or [[BRCA2]] mutation.{{cite book | vauthors = Petrucelli N, Daly MB, Pal T | veditors = Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Mirzaa G, Amemiya A | chapter = BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer | title = GeneReviews | publisher = University of Washington, Seattle | orig-date = September 1998 | date = December 2016 | pmid = 20301425 | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK1247/ }}]] [65] => {{Further|BRCA mutation}} [66] => 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.{{cite web | url = http://www.breastcancer.org/risk/factors/genetics | title = Genetics | date = 2012-09-17 | publisher = Breastcancer.org }} [67] => [68] => 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.{{cite journal | vauthors = Elstrodt F, Hollestelle A, Nagel JH, Gorin M, Wasielewski M, van den Ouweland A, Merajver SD, Ethier SP, Schutte M | display-authors = 6 | title = BRCA1 mutation analysis of 41 human breast cancer cell lines reveals three new deleterious mutants | journal = Cancer Research | volume = 66 | issue = 1 | pages = 41–45 | date = January 2006 | pmid = 16397213 | doi = 10.1158/0008-5472.CAN-05-2853 }} [69] => [70] => 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.{{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 | s2cid = 32023181 | doi-access = free }} Other methods have been proposed: traditional [[quantitative PCR]],{{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 | s2cid = 11583160 }} [[multiplex ligation-dependent probe amplification]] (MLPA),{{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 }} and Quantitative Multiplex PCR of Short Fluorescent Fragments (QMPSF).{{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 | s2cid = 24737909 | doi-access = free }} 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).{{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 | s2cid = 2393567 }} [71] => [72] => 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.{{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 = 3 | pages = 157–63 | year = 2008 | doi = 10.4161/epi.3.3.6387 | pmid = 18567944| s2cid = 35616414 | doi-access = free }} [73] => [74] => 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}} [75] => [76] => 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.{{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 | doi-access = free }} [77] => [78] => 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. [79] => [80] => Women 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.{{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 }} [81] => [82] => As aforementioned, biallelic and homozygous inheritance of the BRCA1 gene leads to FA-S, which is almost always an embryonically lethal condition. [83] => [84] => ==Low expression of ''BRCA1'' in breast and ovarian cancers== [85] => BRCA1 expression is reduced or undetectable in the majority of high grade, ductal breast cancers.{{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 |s2cid=7988460 }} 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.{{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 |doi-access=free }} 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.{{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 |doi-access=free }} 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. [86] => [87] => 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.{{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 |doi-access=free }} 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.{{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 |doi-access=free }} Bowtell{{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 |s2cid=22688947 }} 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. [88] => [89] => In addition to its role in repairing DNA damages, BRCA1 facilitates [[apoptosis]] in breast and ovarian cell lines when cells are stressed by agents, including [[ionizing radiation]], that cause [[DNA damage (naturally occurring)|DNA damages]].Thangaraju M, Kaufmann SH, Couch FJ. BRCA1 facilitates stress-induced apoptosis in breast and ovarian cancer cell lines. J Biol Chem. 2000 Oct 27;275(43):33487-96. doi: 10.1074/jbc.M005824200. PMID: 10938285 [[DNA repair|Repair of DNA damages]] and [[apoptosis]] are two enzymatic processes essential for maintaining [[genome]] integrity in humans. Cells that are deficient in DNA repair tend to accumulate [[DNA damage (naturally occurring)|DNA damages]], and when such cells are also defective in apoptosis they tend to survive even with excess DNA damage.Bernstein C, Bernstein H, Payne CM, Garewal H. DNA repair/pro-apoptotic dual-role proteins in five major DNA repair pathways: fail-safe protection against carcinogenesis. Mutat Res. 2002 Jun;511(2):145-78. doi: 10.1016/s1383-5742(02)00009-1. PMID: 12052432 Replication of DNA in such cells leads to [[mutation]]s and these mutations may cause cancer. Thus BRCA1 appears to have two roles related to the prevention of cancer, where one role is to promote repair of a specific class of damages and the second role is to induce apoptosis if the level of such DNA damage is beyond the cell’s repair capability [90] => [91] => ===Mutation of ''BRCA1'' in breast and ovarian cancer=== [92] => Only about 3%–8% of all women with breast cancer carry a mutation in BRCA1 or BRCA2.{{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|doi-access=free }} Similarly, ''BRCA1'' mutations are only seen in about 18% of ovarian cancers (13% [[germline mutation]]s and 5% somatic mutations).{{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 }} [93] => [94] => Thus, while BRCA1 expression is low in the majority of these cancers, ''BRCA1'' mutation is not a major cause of reduced expression. Certain latent viruses, which are frequently detected in breast cancer tumors, can decrease the expression of the BRCA1 gene and cause the development of breast tumors.{{cite journal | vauthors = Polansky H, Schwab H | title = How latent viruses cause breast cancer: An explanation based on the microcompetition model | journal = Bosnian Journal of Basic Medical Sciences | volume = 19 | issue = 3 | pages = 221–226 | date = August 2019 | pmid = 30579323 | pmc = 6716096 | doi = 10.17305/bjbms.2018.3950 }} [95] => [96] => ===''BRCA1'' promoter hypermethylation in breast and ovarian cancer=== [97] => ''BRCA1'' [[DNA methylation|promoter hypermethylation]] was present in only 13% of unselected primary breast carcinomas.{{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 |author-link13=Stephen B. Baylin |author-link14=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|doi-access=free }} Similarly, ''BRCA1'' promoter hypermethylation was present in only 5% to 15% of EOC cases. [98] => [99] => Thus, while BRCA1 expression is low in these cancers, ''BRCA1'' promoter methylation is only a minor cause of reduced expression. [100] => [101] => ===MicroRNA repression of BRCA1 in breast cancers=== [102] => 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.{{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 }} 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.{{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 }} In breast cancer cell lines, there is an inverse correlation of BRCA1 protein levels with miR-182 expression. 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. [103] => [104] => 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.{{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 }} Thus, miR-146a and/or miR-146b-5p may also contribute to reduced expression of BRCA1 in these triple-negative breast cancers. [105] => [106] => ===MicroRNA repression of BRCA1 in ovarian cancers=== [107] => 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.{{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 |s2cid=206325689 }} In cells with over-expressed miR-182, BRCA1 remained low, even after exposure to ionizing radiation (which normally raises BRCA1 expression). Thus much of the reduced or absent BRCA1 in HG-SOC may be due to over-expressed miR-182. [108] => [109] => Another microRNA known to reduce expression of BRCA1 in ovarian cancer cells is miR-9. 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, so that increased miR-9 may also contribute to reduced expression of BRCA1 in these ovarian cancers. [110] => [111] => ===Deficiency of ''BRCA1'' expression is likely tumorigenic=== [112] => DNA damage appears to be the primary underlying cause of cancer,{{cite journal |vauthors=Kastan MB |title=DNA damage responses: mechanisms and roles in human disease: 2007 G.H.A. Clowes Memorial Award Lecture |journal=Mol. Cancer Res. |volume=6 |issue=4 |pages=517–24 |year=2008 |pmid=18403632 |doi=10.1158/1541-7786.MCR-08-0020 |doi-access=free }} and deficiencies in DNA repair appears to underlie many forms of cancer.{{cite journal |vauthors=Harper JW, Elledge SJ |title=The DNA damage response: ten years after |journal=Mol. Cell |volume=28 |issue=5 |pages=739–45 |year=2007 |pmid=18082599 |doi=10.1016/j.molcel.2007.11.015 |doi-access=free }} If DNA repair is deficient, DNA damage tends to accumulate. Such excess DNA damage may increase [[mutational]] errors during [[DNA replication]] due to error-prone [[DNA repair#Translesion synthesis|translesion synthesis]]. Excess DNA damage may also increase [[Epigenetics|epigenetic]] alterations due to errors during DNA repair.{{cite journal | vauthors = O'Hagan HM, Mohammad HP, Baylin SB | title = Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island | journal = PLOS Genetics | volume = 4 | issue = 8 | pages = e1000155 | year = 2008 | pmid = 18704159 | pmc = 2491723 | doi = 10.1371/journal.pgen.1000155 | doi-access = free }}{{cite journal | vauthors = Cuozzo C, Porcellini A, Angrisano T, Morano A, Lee B, Di Pardo A, Messina S, Iuliano R, Fusco A, Santillo MR, Muller MT, Chiariotti L, Gottesman ME, Avvedimento EV | title = DNA damage, homology-directed repair, and DNA methylation | journal = PLOS Genetics | volume = 3 | issue = 7 | pages = e110 | date = Jul 2007 | pmid = 17616978 | pmc = 1913100 | doi = 10.1371/journal.pgen.0030110 | doi-access = free }} Such mutations and epigenetic alterations may give rise to [[cancer]]. The frequent microRNA-induced deficiency of ''BRCA1'' in breast and ovarian cancers likely contribute to the progression of those cancers. [113] => [114] => ==Germ-line mutations and founder effect== [115] => All germ-line BRCA1 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, in theory, be traced back to a common ancestor. Given the complexity of mutation screening for BRCA1, 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.{{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 | s2cid = 23327569 }} Examples of manifestations of a founder effect are seen among [[Ashkenazi Jews]]. Three mutations in BRCA1 have been reported to account for the majority of Ashkenazi Jewish patients with inherited BRCA1-related breast and/or ovarian cancer: 185delAG, 188del11 and 5382insC in the BRCA1 gene.{{cite journal|vauthors=Struewing JP, Abeliovich D, Peretz T, Avishai N, Kaback MM, Collins FS, Brody LC|date=October 1995|title=The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals|journal=Nat. Genet.|volume=11|issue=2|pages=198–200|doi=10.1038/ng1095-198|pmid=7550349|s2cid=21387351}}{{cite journal | vauthors = Tonin P, Serova O, Lenoir G, Lynch H, Durocher F, Simard J, Morgan K, Narod S | title = BRCA1 mutations in Ashkenazi Jewish women | journal = American Journal of Human Genetics | volume = 57 | issue = 1 | page = 189 | year = 1995 | pmid = 7611288 | pmc = 1801236 }} In fact, it has been shown that if a Jewish woman does not carry a BRCA1 185delAG, BRCA1 5382insC founder mutation, it is highly unlikely that a different BRCA1 mutation will be found.{{cite journal | vauthors = Narod SA, Foulkes WD | title = BRCA1 and BRCA2: 1994 and beyond | journal = Nature Reviews Cancer | volume = 4 | issue = 9 | pages = 665–676 | year = 2004 | pmid = 15343273 | doi = 10.1038/nrc1431 | s2cid = 30686068 }} Additional examples of founder mutations in BRCA1 are given in Table 1 (mainly derived from). [116] => [117] => {{Dynamic list}} [118] => [119] => {| class="wikitable" [120] => |- [121] => ! Population or subgroup !! BRCA1 mutation(s){{cite journal | vauthors = den Dunnen JT, Antonarakis SE | title = Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion | journal = Human Mutation | volume = 15 | issue = 1 | pages = 7–12 | year = 2000 | pmid = 10612815 | doi = 10.1002/(SICI)1098-1004(200001)15:1<7::AID-HUMU4>3.0.CO;2-N | doi-access = free }}!! Reference(s) [122] => |- [123] => | African-Americans || 943ins10, M1775R || {{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 | doi-access = free }} [124] => |- [125] => | Afrikaners || E881X, 1374delC || {{cite journal | vauthors = Reeves MD, Yawitch TM, van der Merwe NC, van den Berg HJ, Dreyer G, van Rensburg EJ | title = BRCA1 mutations in South African breast and/or ovarian cancer families: evidence of a novel founder mutation in Afrikaner families | journal = Int. J. Cancer | volume = 110 | issue = 5 | pages = 677–82 | date = July 2004 | pmid = 15146556 | doi = 10.1002/ijc.20186 | s2cid = 22970255 | doi-access = free }}{{cite journal | vauthors = Francies FZ, Wainstein T, De Leeneer K, Cairns A, Murdoch M, Nietz S, Cubasch H, Poppe B, Van Maerken T, Crombez B, Coene I, Kerr R, Slabbert JP, Vral A, Krause A, Baeyens A | title = BRCA1, BRCA2 and PALB2 mutations and CHEK2 c.1100delC in different South African ethnic groups diagnosed with premenopausal and/or triple negative breast cancer | journal = BMC Cancer | volume = 15 | pages = 912 | date = Nov 2015 | pmid = 26577449 | doi = 10.1186/s12885-015-1913-6 | doi-access = free | pmc=4647511}} [126] => |- [127] => | Ashkenazi Jewish || 185delAG, 188del11, 5382insC || [128] => |- [129] => | Austrians || 2795delA, C61G, 5382insC, Q1806stop || {{cite journal | vauthors = Wagner TM, Möslinger RA, Muhr D, Langbauer G, Hirtenlehner K, Concin H, Doeller W, Haid A, Lang AH, Mayer P, Ropp E, Kubista E, Amirimani B, Helbich T, Becherer A, Scheiner O, Breiteneder H, Borg A, Devilee P, Oefner P, Zielinski C | title = BRCA1-related breast cancer in Austrian breast and ovarian cancer families: specific BRCA1 mutations and pathological characteristics | journal = International Journal of Cancer | volume = 77 | issue = 3 | pages = 354–360 | year = 1998 | pmid = 9663595 | doi = 10.1002/(SICI)1097-0215(19980729)77:3<354::AID-IJC8>3.0.CO;2-N | doi-access = free }} [130] => |- [131] => | Belgians || 2804delAA, IVS5+3A>G || {{cite journal | vauthors = Peelen T, van Vliet M, Petrij-Bosch A, Mieremet R, Szabo C, van den Ouweland AM, Hogervorst F, Brohet R, Ligtenberg MJ, Teugels E, van der Luijt R, van der Hout AH, Gille JJ, Pals G, Jedema I, Olmer R, van Leeuwen I, Newman B, Plandsoen M, van der Est M, Brink G, Hageman S, Arts PJ, Bakker MM, Devilee P | title = A high proportion of novel mutations in BRCA1 with strong founder effects among Dutch and Belgian hereditary breast and ovarian cancer families | journal = American Journal of Human Genetics | volume = 60 | issue = 5 | pages = 1041–1049 | year = 1997 | pmid = 9150151 | pmc = 1712432 }}{{cite journal | vauthors = Claes K, Machackova E, De Vos M, Poppe B, De Paepe A, Messiaen L | title = Mutation analysis of the BRCA1 and BRCA2 genes in the Belgian patient population and identification of a Belgian founder mutation BRCA1 IVS5 + 3A > G | journal = Disease Markers | volume = 15 | issue = 1–3 | pages = 69–73 | year = 1999 | pmid = 10595255 | pmc = 3851655 | doi = 10.1155/1999/241046 | doi-access = free }} [132] => |- [133] => | Dutch || Exon 2 deletion, exon 13 deletion, 2804delAA || {{cite journal | vauthors = Petrij-Bosch A, Peelen T, van Vliet M, van Eijk R, Olmer R, Drüsedau M, Hogervorst FB, Hageman S, Arts PJ, Ligtenberg MJ, Meijers-Heijboer H, Klijn JG, Vasen HF, Cornelisse CJ, van 't Veer LJ, Bakker E, van Ommen GJ, Devilee P | title = BRCA1 genomic deletions are major founder mutations in Dutch breast cancer patients | journal = Nature Genetics | volume = 17 | issue = 3 | pages = 341–345 | year = 1997 | pmid = 9354803 | doi = 10.1038/ng1197-341 | hdl = 1765/54808 | s2cid = 13028232 | url = https://repub.eur.nl/pub/54808/ng1197-341.pdf }}{{cite journal | vauthors = Verhoog LC, van den Ouweland AM, Berns E, van Veghel-Plandsoen MM, van Staveren IL, Wagner A, Bartels CC, Tilanus-Linthorst MM, Devilee P, Seynaeve C, Halley DJ, Niermeijer MF, Klijn JG, Meijers-Heijboer H | title = Large regional differences in the frequency of distinct BRCA1/BRCA2 mutations in 517 Dutch breast and/or ovarian cancer families | journal = European Journal of Cancer | volume = 37 | issue = 16 | pages = 2082–2090 | year = 2001 | pmid = 11597388 | doi = 10.1016/S0959-8049(01)00244-1 }} [134] => |- [135] => | Finns || 3745delT, IVS11-2A>G || {{cite journal | vauthors = Huusko P, Pääkkönen K, Launonen V, Pöyhönen M, Blanco G, Kauppila A, Puistola U, Kiviniemi H, Kujala M, Leisti J, Winqvist R | title = Evidence of founder mutations in Finnish BRCA1 and BRCA2 families | journal = American Journal of Human Genetics | volume = 62 | issue = 6 | pages = 1544–1548 | year = 1998 | pmid = 9585608 | pmc = 1377159 | doi = 10.1086/301880 }}{{cite journal | vauthors = Pääkkönen K, Sauramo S, Sarantaus L, Vahteristo P, Hartikainen A, Vehmanen P, Ignatius J, Ollikainen V, Kääriäinen H, Vauramo E, Nevanlinna H, Krahe R, Holli K, Kere J | title = Involvement of BRCA1 and BRCA2 in breast cancer in a western Finnish sub-population | journal = Genetic Epidemiology | volume = 20 | issue = 2 | pages = 239–246 | year = 2001 | pmid = 11180449 | doi = 10.1002/1098-2272(200102)20:2<239::AID-GEPI6>3.0.CO;2-Y | s2cid = 41804152 }} [136] => |- [137] => | French || 3600del11, G1710X || {{cite journal | vauthors = Muller D, Bonaiti-Pellié C, Abecassis J, Stoppa-Lyonnet D, Fricker JP | title = BRCA1 testing in breast and/or ovarian cancer families from northeastern France identifies two common mutations with a founder effect | journal = Familial Cancer | volume = 3 | issue = 1 | pages = 15–20 | year = 2004 | pmid = 15131401 | doi = 10.1023/B:FAME.0000026819.44213.df | s2cid = 24615109 }} [138] => |- [139] => | French Canadians || C4446T || {{cite journal | vauthors = Tonin PN, Mes-Masson AM, Narod SA, Ghadirian P, Provencher D | title = Founder BRCA1 and BRCA2 mutations in French Canadian ovarian cancer cases unselected for family history | journal = Clinical Genetics | volume = 55 | issue = 5 | pages = 318–324 | year = 1999 | pmid = 10422801 | doi = 10.1034/j.1399-0004.1999.550504.x | s2cid = 23931343 }} [140] => |- [141] => | Germans || 5382insC, 4184del4 || {{cite journal | vauthors = Backe J, Hofferbert S, Skawran B, Dörk T, Stuhrmann M, Karstens JH, Untch M, Meindl A, Burgemeister R, Chang-Claude J, Weber BH | title = Frequency of BRCA1 mutation 5382insC in German breast cancer patients | journal = Gynecologic Oncology | volume = 72 | issue = 3 | pages = 402–406 | year = 1999 | pmid = 10053113 | doi = 10.1006/gyno.1998.5270 }}{{cite web | url = http://mutview.dmb.med.keio.ac.jp/MutationView/jsp/mutview/html/brca1.html | title = Mutation data of the BRCA1 gene | work = KMDB/MutationView (Keio Mutation Databases) | publisher = Keio University }} [142] => |- [143] => | Greeks || 5382insC || {{cite journal | vauthors = Ladopoulou A, Kroupis C, Konstantopoulou I, Ioannidou-Mouzaka L, Schofield AC, Pantazidis A, Armaou S, Tsiagas I, Lianidou E, Efstathiou E, Tsionou C, Panopoulos C, Mihalatos M, Nasioulas G, Skarlos D, Haites NE, Fountzilas G, Pandis N, Yannoukakos D | title = Germ line BRCA1 and BRCA2 mutations in Greek breast/ovarian cancer families: 5382insC is the most frequent mutation observed | journal = Cancer Letters | volume = 185 | issue = 1 | pages = 61–70 | year = 2002 | pmid = 12142080 | doi = 10.1016/S0304-3835(01)00845-X }} [144] => |- [145] => | Hungarians || 300T>G, 5382insC, 185delAG || {{cite journal | vauthors = Van Der Looij M, Szabo C, Besznyak I, Liszka G, Csokay B, Pulay T, Toth J, Devilee P, King MC, Olah E | title = Prevalence of founder BRCA1 and BRCA2 mutations among breast and ovarian cancer patients in Hungary | journal = International Journal of Cancer | volume = 86 | issue = 5 | pages = 737–740 | year = 2000 | pmid = 10797299 | doi = 10.1002/(SICI)1097-0215(20000601)86:5<737::AID-IJC21>3.0.CO;2-1 | s2cid = 25394976 | doi-access = free }} [146] => |- [147] => | Italians || 5083del19 || {{cite journal | vauthors = Baudi F, Quaresima B, Grandinetti C, Cuda G, Faniello C, Tassone P, Barbieri V, Bisegna R, Ricevuto E, Conforti S, Viel A, Marchetti P, Ficorella C, Radice P, Costanzo F, Venuta S | title = Evidence of a founder mutation of BRCA1 in a highly homogeneous population from southern Italy with breast/ovarian cancer | journal = Human Mutation | volume = 18 | issue = 2 | pages = 163–164 | year = 2001 | pmid = 11462242 | doi = 10.1002/humu.1167 | s2cid = 2995 | doi-access = free }} [148] => |- [149] => | Japanese || L63X, Q934X || {{cite journal | vauthors = Sekine M, Nagata H, Tsuji S, Hirai Y, Fujimoto S, Hatae M, Kobayashi I, Fujii T, Nagata I, Ushijima K, Obata K, Suzuki M, Yoshinaga M, Umesaki N, Satoh S, Enomoto T, Motoyama S, Tanaka K | title = Mutational analysis of BRCA1 and BRCA2 and clinicopathologic analysis of ovarian cancer in 82 ovarian cancer families: two common founder mutations of BRCA1 in Japanese population | journal = Clinical Cancer Research | volume = 7 | issue = 10 | pages = 3144–3150 | year = 2001 | pmid = 11595708 }} [150] => |- [151] => | Native North Americans || 1510insG, 1506A>G || {{cite journal | vauthors = Liede A, Jack E, Hegele RA, Narod SA | title = A BRCA1 mutation in Native North American families | journal = Human Mutation | volume = 19 | issue = 4 | page = 460 | year = 2002 | pmid = 11933205 | doi = 10.1002/humu.9027 | s2cid = 37710898 | doi-access = free }} [152] => |- [153] => | Northern Irish || 2800delAA || {{cite journal |author=The Scottish/Northern Irish BRCA1/BRCA2 Consortium | title = BRCA1 and BRCA2 mutations in Scotland and Northern Ireland | journal = British Journal of Cancer | volume = 88 | issue = 8 | pages = 1256–1262 | year = 2003 | pmid = 12698193 | pmc = 2747571 | doi = 10.1038/sj.bjc.6600840 }} [154] => |- [155] => | Norwegians || 816delGT, 1135insA, 1675delA, 3347delAG || {{cite journal | vauthors = Borg A, Dørum A, Heimdal K, Maehle L, Hovig E, Møller P | title = BRCA1 1675delA and 1135insA account for one third of Norwegian familial breast-ovarian cancer and are associated with later disease onset than less frequent mutations | journal = Disease Markers | volume = 15 | issue = 1–3 | pages = 79–84 | year = 1999 | pmid = 10595257 | pmc = 3851406 | doi = 10.1155/1999/278269 | doi-access = free }}{{cite journal | vauthors = Heimdal K, Maehle L, Apold J, Pedersen JC, Møller P | title = The Norwegian founder mutations in BRCA1: high penetrance confirmed in an incident cancer series and differences observed in the risk of ovarian cancer | journal = European Journal of Cancer | volume = 39 | issue = 15 | pages = 2205–2213 | year = 2003 | pmid = 14522380 | doi = 10.1016/S0959-8049(03)00548-3 }} [156] => |- [157] => | Pakistanis || 2080insA, 3889delAG, 4184del4, 4284delAG, IVS14-1A>G || {{cite journal | vauthors = Liede A, Malik IA, Aziz Z, Rios Pd Pde L, Kwan E, Narod SA | title = Contribution of BRCA1 and BRCA2 Mutations to Breast and Ovarian Cancer in Pakistan | journal = American Journal of Human Genetics | volume = 71 | issue = 3 | pages = 595–606 | year = 2002 | pmid = 12181777 | pmc = 379195 | doi = 10.1086/342506 }} [158] => |- [159] => | Poles || 300T>G, 5382insC, C61G, 4153delA || {{cite journal | vauthors = Górski B, Byrski T, Huzarski T, Jakubowska A, Menkiszak J, Gronwald J, Pluzańska A, Bebenek M, Fischer-Maliszewska L, Grzybowska E, Narod SA, Lubiński J | title = Founder mutations in the BRCA1 gene in Polish families with breast-ovarian cancer | journal = American Journal of Human Genetics | volume = 66 | issue = 6 | pages = 1963–1968 | year = 2000 | pmid = 10788334 | pmc = 1378051 | doi = 10.1086/302922 }}{{cite journal | vauthors = Perkowska M, BroZek I, Wysocka B, Haraldsson K, Sandberg T, Johansson U, Sellberg G, Borg A, Limon J | title = BRCA1 and BRCA2 mutation analysis in breast-ovarian cancer families from northeastern Poland | journal = Hum. Mutat. | volume = 21 | issue = 5 | pages = 553–4 | date = May 2003 | pmid = 12673801 | doi = 10.1002/humu.9139 | s2cid = 7001156 | doi-access = free }} [160] => |- [161] => | Russians || 5382insC, 4153delA || {{cite journal | vauthors = Gayther SA, Harrington P, Russell P, Kharkevich G, Garkavtseva RF, Ponder BA | title = Frequently occurring germ-line mutations of the BRCA1 gene in ovarian cancer families from Russia | journal = Am. J. Hum. Genet. | volume = 60 | issue = 5 | pages = 1239–42 | date = May 1997 | pmid = 9150173 | pmc = 1712436 }} [162] => |- [163] => | Scots || 2800delAA || {{cite journal | vauthors = Liede A, Cohen B, Black DM, Davidson RH, Renwick A, Hoodfar E, Olopade OI, Micek M, Anderson V, De Mey R, Fordyce A, Warner E, Dann JL, King MC, Weber B, Narod SA, Steel CM | title = Evidence of a founder BRCA1 mutation in Scotland | journal = Br. J. Cancer | volume = 82 | issue = 3 | pages = 705–11 | date = February 2000 | pmid = 10682686 | pmc = 2363321 | doi = 10.1054/bjoc.1999.0984 }} [164] => |- [165] => | Spaniards || R71G || {{cite journal | vauthors = Vega A, Campos B, Bressac-De-Paillerets B, Bond PM, Janin N, Douglas FS, Domènech M, Baena M, Pericay C, Alonso C, Carracedo A, Baiget M, Diez O | title = The R71G BRCA1 is a founder Spanish mutation and leads to aberrant splicing of the transcript | journal = Hum. Mutat. | volume = 17 | issue = 6 | pages = 520–1 | date = June 2001 | pmid = 11385711 | doi = 10.1002/humu.1136 | s2cid = 39462456 | doi-access = free }}{{cite journal | vauthors = Campos B, Díez O, Odefrey F, Domènech M, Moncoutier V, Martínez-Ferrandis JI, Osorio A, Balmaña J, Barroso A, Armengod ME, Benítez J, Alonso C, Stoppa-Lyonnet D, Goldgar D, Baiget M | title = Haplotype analysis of the BRCA2 9254delATCAT recurrent mutation in breast/ovarian cancer families from Spain | journal = Hum. Mutat. | volume = 21 | issue = 4 | page = 452 | date = April 2003 | pmid = 12655574 | doi = 10.1002/humu.9133 | s2cid = 34333797 | doi-access = free }} [166] => |- [167] => | Swedes || Q563X, 3171ins5, 1201del11, 2594delC || {{cite journal | vauthors = Bergman A, Einbeigi Z, Olofsson U, Taib Z, Wallgren A, Karlsson P, Wahlström J, Martinsson T, Nordling M | title = The western Swedish BRCA1 founder mutation 3171ins5; a 3.7 cM conserved haplotype of today is a reminiscence of a 1500-year-old mutation | journal = Eur. J. Hum. Genet. | volume = 9 | issue = 10 | pages = 787–93 | date = October 2001 | pmid = 11781691 | doi = 10.1038/sj.ejhg.5200704 | doi-access = free }} [168] => |} [169] => [170] => ==Female fertility== [171] => As women age, reproductive performance declines, leading to menopause. This decline is tied to a reduction in the number of ovarian follicles. Although about 1 million oocytes are present at birth in the human ovary, only about 500 (about 0.05%) of these ovulate. The decline in ovarian reserve appears to occur at a constantly increasing rate with age,{{cite journal | vauthors = Hansen KR, Knowlton NS, Thyer AC, Charleston JS, Soules MR, Klein NA | title = A new model of reproductive aging: the decline in ovarian non-growing follicle number from birth to menopause | journal = Hum. Reprod. | volume = 23 | issue = 3 | pages = 699–708 | date = March 2008 | pmid = 18192670 | doi = 10.1093/humrep/dem408 | doi-access = free }} and leads to nearly complete exhaustion of the reserve by about age 52. As ovarian reserve and fertility decline with age, there is also a parallel increase in pregnancy failure and meiotic errors, resulting in chromosomally abnormal conceptions.{{cite journal | vauthors = Hassold T, Hunt P | title = Maternal age and chromosomally abnormal pregnancies: what we know and what we wish we knew | journal = Current Opinion in Pediatrics | volume = 21 | issue = 6 | pages = 703–8 | date = December 2009 | pmid = 19881348 | pmc = 2894811 | doi = 10.1097/MOP.0b013e328332c6ab }} [172] => [173] => Women with a germ-line ''BRCA1'' mutation appear to have a diminished oocyte reserve and decreased fertility compared to normally aging women.{{cite journal | vauthors = Oktay K, Kim JY, Barad D, Babayev SN | title = Association of BRCA1 mutations with occult primary ovarian insufficiency: a possible explanation for the link between infertility and breast/ovarian cancer risks | journal = J. Clin. Oncol. | volume = 28 | issue = 2 | pages = 240–4 | date = January 2010 | pmid = 19996028 | pmc = 3040011 | doi = 10.1200/JCO.2009.24.2057 }} Furthermore, women with an inherited ''BRCA1'' mutation undergo menopause prematurely.{{cite journal | vauthors = Rzepka-Górska I, Tarnowski B, Chudecka-Głaz A, Górski B, Zielińska D, Tołoczko-Grabarek A | title = Premature menopause in patients with BRCA1 gene mutation | journal = Breast Cancer Res. Treat. | volume = 100 | issue = 1 | pages = 59–63 | date = November 2006 | pmid = 16773440 | doi = 10.1007/s10549-006-9220-1 | s2cid = 19572648 }} Since BRCA1 is a key DNA repair protein, these findings suggest that naturally occurring DNA damages in oocytes are repaired less efficiently in women with a ''BRCA1'' defect, and that this repair inefficiency leads to early reproductive failure. [174] => [175] => As noted above, the BRCA1 protein plays a key role in homologous recombinational repair. This is the only known cellular process that can accurately repair DNA double-strand breaks. DNA double-strand breaks accumulate with age in humans and mice in primordial follicles.{{cite journal | vauthors = Titus S, Li F, Stobezki R, Akula K, Unsal E, Jeong K, Dickler M, Robson M, Moy F, Goswami S, Oktay K | title = Impairment of BRCA1-related DNA double-strand break repair leads to ovarian aging in mice and humans | journal = Sci Transl Med | volume = 5 | issue = 172 | pages = 172ra21 | date = February 2013 | pmid = 23408054 | doi = 10.1126/scitranslmed.3004925 | pmc=5130338}} Primordial follicles contain oocytes that are at an intermediate (prophase I) stage of meiosis. Meiosis is the general process in eukaryotic organisms by which germ cells are formed, and it is likely an adaptation for removing DNA damages, especially double-strand breaks, from germ line DNA.Bernstein H; Hopf FA; Michod RE (1987). The Molecular Basis of the Evolution of Sex. Adv. Genet. Advances in Genetics. Vol. 24. pp. 323–70. doi:10.1016/S0065-2660(08)60012-7. ISBN 9780120176243. PMID 3324702 (Also see article [[Meiosis]]). Homologous recombinational repair employing BRCA1 is especially promoted during meiosis. It was found that expression of four key genes necessary for homologous recombinational repair of DNA double-strand breaks (''BRCA1, MRE11, RAD51'' and ''ATM'') decline with age in the oocytes of humans and mice, leading to the hypothesis that DNA double-strand break repair is necessary for the maintenance of oocyte reserve and that a decline in efficiency of repair with age plays a role in ovarian aging. [176] => [177] => ==Cancer chemotherapy== [178] => Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths worldwide. At diagnosis, almost 70% of persons with NSCLC have locally advanced or metastatic disease. Persons with NSCLC are often treated with therapeutic platinum compounds (e.g. cisplatin, carboplatin or oxaliplatin) that cause inter-strand cross-links in DNA. Among individuals with NSCLC, low expression of ''BRCA1'' in the primary tumor correlated with improved survival after platinum-containing chemotherapy.{{cite journal | vauthors = Taron M, Rosell R, Felip E, Mendez P, Souglakos J, Ronco MS, Queralt C, Majo J, Sanchez JM, Sanchez JJ, Maestre J | title = BRCA1 mRNA expression levels as an indicator of chemoresistance in lung cancer | journal = Hum. Mol. Genet. | volume = 13 | issue = 20 | pages = 2443–9 | date = October 2004 | pmid = 15317748 | doi = 10.1093/hmg/ddh260 | doi-access = free }}{{cite journal | vauthors = Papadaki C, Sfakianaki M, Ioannidis G, Lagoudaki E, Trypaki M, Tryfonidis K, Mavroudis D, Stathopoulos E, Georgoulias V, Souglakos J | title = ERCC1 and BRAC1 mRNA expression levels in the primary tumor could predict the effectiveness of the second-line cisplatin-based chemotherapy in pretreated patients with metastatic non-small cell lung cancer | journal = J Thorac Oncol | volume = 7 | issue = 4 | pages = 663–71 | date = April 2012 | pmid = 22425915 | doi = 10.1097/JTO.0b013e318244bdd4 | doi-access = free }} This correlation implies that low BRCA1 in cancer, and the consequent low level of DNA repair, causes vulnerability of cancer to treatment by the DNA cross-linking agents. High BRCA1 may protect cancer cells by acting in a pathway that removes the damages in DNA introduced by the platinum drugs. Thus the level of ''BRCA1'' expression is a potentially important tool for tailoring chemotherapy in lung cancer management. [179] => [180] => Level of ''BRCA1'' expression is also relevant to ovarian cancer treatment. Patients having sporadic ovarian cancer who were treated with platinum drugs had longer median survival times if their ''BRCA1'' expression was low compared to patients with higher ''BRCA1'' expression (46 compared to 33 months).{{cite journal | vauthors = Weberpals J, Garbuio K, O'Brien A, Clark-Knowles K, Doucette S, Antoniouk O, Goss G, Dimitroulakos J | title = The DNA repair proteins BRCA1 and ERCC1 as predictive markers in sporadic ovarian cancer | journal = Int. J. Cancer | volume = 124 | issue = 4 | pages = 806–15 | date = February 2009 | pmid = 19035454 | doi = 10.1002/ijc.23987 | s2cid = 13357407 | doi-access = free }} [181] => [182] => ==Patents, enforcement, litigation, and controversy== [183] => {{Main|Association for Molecular Pathology v. Myriad Genetics}} [184] => A patent application for the isolated BRCA1 gene and cancer promoting mutations discussed above, as well as methods to diagnose the likelihood of getting breast cancer, was filed by the University of Utah, National Institute of Environmental Health Sciences (NIEHS) and [[Myriad Genetics]] in 1994;{{Ref patent | country = US | number = 5747282 | status = patent | title = 7Q-linked breast and ovarian cancer susceptibility gene | pubdate = | gdate = 1998-05-05 | fdate = 1995-06-07 | pridate = | inventor = Skolnick HS, Goldgar DE, Miki Y, Swenson J, Kamb A, Harshman KD, Shattuck-Eidens DM, Tavtigian SV, Wiseman RW, Futreal PA | assign1 = Myriad Genetics, Inc., The United States of America as represented by the Secretary of Health and Human Services, | assign2 = University of Utah Research Foundation }} over the next year, Myriad, (in collaboration with investigators at Endo Recherche, Inc., HSC Research & Development Limited Partnership, and University of Pennsylvania), isolated and sequenced the [[BRCA2]] gene and identified key mutations, and the first BRCA2 patent was filed in the U.S. by Myriad and other institutions in 1995.{{cite patent | country = US | number = 5837492 | status = patent | title = Chromosome 13-linked breast cancer susceptibility gene | gdate = 1998-11-17 | fdate = 1996-04-29 | inventor = Tavtigian SV, Kamb A, Simard J, Couch F, Rommens JM, Weber BL | assign1 = Myriad Genetics, Inc., Endo Recherche, Inc., HSC Research & Development Limited Partnership, Trustees of the University of Pennsylvania }} Myriad is the exclusive licensee of these [[Biological patent|patents]] and has enforced them in the US against clinical diagnostic labs. This business model led from Myriad being a startup in 1994 to being a publicly traded company with 1200 employees and about $500M in annual revenue in 2012; it also led to controversy over high prices and the inability to get second opinions from other diagnostic labs, which in turn led to the landmark ''[[Association for Molecular Pathology v. Myriad Genetics]]'' lawsuit.{{cite news | url =http://edition.cnn.com/2009/HEALTH/05/12/us.genes.lawsuit/index.html | title = ACLU sues over patents on breast cancer genes | publisher = CNN | access-date = 2009-05-14| archive-url= https://web.archive.org/web/20090515095043/http://edition.cnn.com/2009/HEALTH/05/12/us.genes.lawsuit/index.html | archive-date= 15 May 2009 | url-status= live}} The patents began to expire in 2014. [185] => [186] => According to an article published in the journal, ''Genetic Medicine'', in 2010, "The patent story outside the United States is more complicated.... For example, patents have been obtained but the patents are being ignored by provincial health systems in Canada. In Australia and the UK, Myriad's licensee permitted use by health systems but announced a change of plans in August 2008. Only a single mutation has been patented in Myriad's lone European-wide patent, although some patents remain under review of an opposition proceeding. In effect, the United States is the only jurisdiction where Myriad's strong patent position has conferred sole-provider status."{{cite journal | vauthors = Cook-Deegan R, DeRienzo C, Carbone J, Chandrasekharan S, Heaney C, Conover C | title = Impact of gene patents and licensing practices on access to genetic testing for inherited susceptibility to cancer: comparing breast and ovarian cancers with colon cancers | journal = Genetics in Medicine | volume = 12 | issue = 4 Suppl | pages = S15–S38 | date = April 2010 | pmid = 20393305 | pmc = 3047448 | doi = 10.1097/GIM.0b013e3181d5a67b }}{{cite journal | vauthors = Benowitz S | title = European groups oppose Myriad's latest patent on BRCA1 | journal = J. Natl. Cancer Inst. | volume = 95 | issue = 1 | pages = 8–9 | date = January 2003 | pmid = 12509391 | doi = 10.1093/jnci/95.1.8 }} Peter Meldrum, CEO of Myriad Genetics, has acknowledged that Myriad has "other competitive advantages that may make such [patent] enforcement unnecessary" in Europe.{{cite web |vauthors=Conley J, Vorhous D, Cook-Deegan J | title = How Will Myriad Respond to the Next Generation of BRCA Testing?|url=http://www.genomicslawreport.com/index.php/2011/03/01/how-will-myriad-respond-to-the-next-generation-of-brca-testing/ | publisher = Robinson, Bradshaw, and Hinson | date = March 2011 | access-date = 2012-12-09 }} [187] => [188] => As with any gene, finding variation in BRCA1 is not hard. The real value comes from understanding what the clinical consequences of any particular variant are. Myriad has a large, proprietary database of such genotype-phenotype correlations. In response, parallel open-source databases are being developed. [189] => [190] => Legal decisions surrounding the BRCA1 and BRCA2 patents will affect the field of [[genetic testing]] in general.{{cite web | url = http://www.ornl.gov/sci/techresources/Human_Genome/elsi/patents.shtml | title = Genetics and Patenting | date = 2010-07-07 | work = Human Genome Project Information | publisher = U.S. Department of Energy Genome Programs }} A June 2013 article, in ''Association for Molecular Pathology v. Myriad Genetics'' (No. 12-398), quoted the [[Supreme Court of the United States|US Supreme Court]]'s unanimous ruling that, "A naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated," invalidating Myriad's patents on the BRCA1 and BRCA2 genes. However, the Court also held that manipulation of a gene to create something not found in nature could still be eligible for patent protection.{{cite news | vauthors = Liptak A |title=Supreme Court Rules Human Genes May Not Be Patented|url=https://www.nytimes.com/2013/06/14/us/supreme-court-rules-human-genes-may-not-be-patented.html|access-date=June 13, 2013|newspaper=[[The New York Times]]|date=June 13, 2013}} The [[Federal Court of Australia]] came to the opposite conclusion, upholding the validity of an Australian Myriad Genetics patent over the BRCA1 gene in February 2013.{{cite news|title = Landmark patent ruling over breast cancer gene BRCA1|date = February 15, 2013| vauthors = Corderoy A |url = http://www.smh.com.au/national/health/landmark-patent-ruling-over-breast-cancer-gene-brca1-20130215-2egsq.html|access-date = June 14, 2013|newspaper = [[Sydney Morning Herald]]}} The Federal Court also rejected an appeal in September 2014.{{cite news|title = Australian federal court rules isolated genetic material can be patented|date = 5 September 2014|url = https://www.theguardian.com/world/2014/sep/05/court-rules-breast-cancer-gene-brca1-patented-australia|access-date = 14 September 2014|newspaper = [[The Guardian]]}} Yvonne D'Arcy won her case against US-based biotech company Myriad Genetics in the [[High Court of Australia]]. In their unanimous decision on October 7, 2015, the "high court found that an isolated nucleic acid, coding for a BRCA1 protein, with specific variations from the norm that are indicative of susceptibility to breast cancer and ovarian cancer was not a 'patentable invention.'"{{cite news | url=https://www.theguardian.com/society/2015/oct/07/patient-wins-high-court-challenge-against-companys-cancer-gene-patent | title=Patient wins high court challenge against company's cancer gene patent | work=The Guardian | date=7 October 2015 | access-date=6 October 2015}} [191] => [192] => ==Interactions== [193] => BRCA1 has been shown to [[protein–protein interaction|interact]] with the following proteins: [194] => {{div col|colwidth=20em}} [195] => * [[Abl gene|ABL1]]{{cite journal | vauthors = Foray N, Marot D, Randrianarison V, Venezia ND, Picard D, Perricaudet M, Favaudon V, Jeggo P | title = Constitutive association of BRCA1 and c-Abl and its ATM-dependent disruption after irradiation | journal = Mol. Cell. Biol. | volume = 22 | issue = 12 | pages = 4020–32 | date = June 2002 | pmid = 12024016 | pmc = 133860 | doi = 10.1128/MCB.22.12.4020-4032.2002 }} [196] => * [[AKT1]]{{cite journal | vauthors = Altiok S, Batt D, Altiok N, Papautsky A, Downward J, Roberts TM, Avraham H | title = Heregulin induces phosphorylation of BRCA1 through phosphatidylinositol 3-Kinase/AKT in breast cancer cells | journal = J. Biol. Chem. | volume = 274 | issue = 45 | pages = 32274–8 | date = November 1999 | pmid = 10542266 | doi = 10.1074/jbc.274.45.32274 | doi-access = free }}{{cite journal | vauthors = Xiang T, Ohashi A, Huang Y, Pandita TK, Ludwig T, Powell SN, Yang Q | title = Negative Regulation of AKT Activation by BRCA1 | journal = Cancer Res. | volume = 68 | issue = 24 | pages = 10040–4 | date = December 2008 | pmid = 19074868 | pmc = 2605656 | doi = 10.1158/0008-5472.CAN-08-3009 }} [197] => * [[Androgen receptor|AR]]{{cite journal | vauthors = Yeh S, Hu YC, Rahman M, Lin HK, Hsu CL, Ting HJ, Kang HY, Chang C | title = Increase of androgen-induced cell death and androgen receptor transactivation by BRCA1 in prostate cancer cells | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 97 | issue = 21 | pages = 11256–61 | date = October 2000 | pmid = 11016951 | pmc = 17187 | doi = 10.1073/pnas.190353897 | bibcode = 2000PNAS...9711256Y | doi-access = free }} [198] => * [[Ataxia telangiectasia and Rad3 related|ATR]] [199] => * [[Ataxia telangiectasia mutated|ATM]]{{cite journal | vauthors = Kim ST, Lim DS, Canman CE, Kastan MB | title = Substrate specificities and identification of putative substrates of ATM kinase family members | journal = J. Biol. Chem. | volume = 274 | issue = 53 | pages = 37538–43 | date = December 1999 | pmid = 10608806 | doi = 10.1074/jbc.274.53.37538 | doi-access = free }}{{cite journal | vauthors = Tibbetts RS, Cortez D, Brumbaugh KM, Scully R, Livingston D, Elledge SJ, Abraham RT | title = Functional interactions between BRCA1 and the checkpoint kinase ATR during genotoxic stress | journal = Genes Dev. | volume = 14 | issue = 23 | pages = 2989–3002 | date = December 2000 | pmid = 11114888 | pmc = 317107 | doi = 10.1101/gad.851000 }}{{cite journal | vauthors = Chen J | title = Ataxia telangiectasia-related protein is involved in the phosphorylation of BRCA1 following deoxyribonucleic acid damage | journal = Cancer Res. | volume = 60 | issue = 18 | pages = 5037–9 | date = September 2000 | pmid = 11016625 }}{{cite journal | vauthors = Gatei M, Zhou BB, Hobson K, Scott S, Young D, Khanna KK | title = Ataxia telangiectasia mutated (ATM) kinase and ATM and Rad3 related kinase mediate phosphorylation of Brca1 at distinct and overlapping sites. In vivo assessment using phospho-specific antibodies | journal = J. Biol. Chem. | volume = 276 | issue = 20 | pages = 17276–80 | date = May 2001 | pmid = 11278964 | doi = 10.1074/jbc.M011681200 | doi-access = free }}{{cite journal | vauthors = Gatei M, Scott SP, Filippovitch I, Soronika N, Lavin MF, Weber B, Khanna KK | title = Role for ATM in DNA damage-induced phosphorylation of BRCA1 | journal = Cancer Res. | volume = 60 | issue = 12 | pages = 3299–304 | date = June 2000 | pmid = 10866324 }}{{cite journal | vauthors = Cortez D, Wang Y, Qin J, Elledge SJ | title = Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks | journal = Science | volume = 286 | issue = 5442 | pages = 1162–6 | date = November 1999 | pmid = 10550055 | doi = 10.1126/science.286.5442.1162 }} [200] => * [[ATF1]]{{cite journal | vauthors = Houvras Y, Benezra M, Zhang H, Manfredi JJ, Weber BL, Licht JD | title = BRCA1 physically and functionally interacts with ATF1 | journal = J. Biol. Chem. | volume = 275 | issue = 46 | pages = 36230–7 | date = November 2000 | pmid = 10945975 | doi = 10.1074/jbc.M002539200 | doi-access = free }} [201] => * [[BACH1]] [202] => * [[BARD1]]{{cite journal | vauthors = Cantor SB, Bell DW, Ganesan S, Kass EM, Drapkin R, Grossman S, Wahrer DC, Sgroi DC, Lane WS, Haber DA, Livingston DM | title = BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function | journal = Cell | volume = 105 | issue = 1 | pages = 149–60 | date = April 2001 | pmid = 11301010 | doi = 10.1016/S0092-8674(01)00304-X | doi-access = free }} [203] => * [[BRCA2]]{{cite journal | vauthors = Sarkisian CJ, Master SR, Huber LJ, Ha SI, Chodosh LA | title = Analysis of murine Brca2 reveals conservation of protein–protein interactions but differences in nuclear localization signals | journal = J. Biol. Chem. | volume = 276 | issue = 40 | pages = 37640–8 | date = October 2001 | pmid = 11477095 | doi = 10.1074/jbc.M106281200 | doi-access = free }} [204] => * [[BRCC3]] [205] => * [[BRE (gene)|BRE]] [206] => * [[BRIP1]]{{cite journal | vauthors = Botuyan MV, Nominé Y, Yu X, Juranic N, Macura S, Chen J, Mer G | title = Structural basis of BACH1 phosphopeptide recognition by BRCA1 tandem BRCT domains | journal = Structure | volume = 12 | issue = 7 | pages = 1137–46 | date = July 2004 | pmid = 15242590 | pmc = 3652423 | doi = 10.1016/j.str.2004.06.002 }}{{cite journal | vauthors = Yu X, Chini CC, He M, Mer G, Chen J | title = The BRCT domain is a phospho-protein binding domain | journal = Science | volume = 302 | issue = 5645 | pages = 639–42 | date = October 2003 | pmid = 14576433 | doi = 10.1126/science.1088753 | bibcode = 2003Sci...302..639Y | s2cid = 29407635 }}{{cite journal | vauthors = Clapperton JA, Manke IA, Lowery DM, Ho T, Haire LF, Yaffe MB, Smerdon SJ | title = Structure and mechanism of BRCA1 BRCT domain recognition of phosphorylated BACH1 with implications for cancer | journal = Nature Structural & Molecular Biology | volume = 11 | issue = 6 | pages = 512–8 | date = June 2004 | pmid = 15133502 | doi = 10.1038/nsmb775 | s2cid = 7354915 }} [207] => * [[C-jun]] [208] => * [[CHEK2]]{{cite journal | vauthors = Lee JS, Collins KM, Brown AL, Lee CH, Chung JH | title = hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response | journal = Nature | volume = 404 | issue = 6774 | pages = 201–4 | date = March 2000 | pmid = 10724175 | doi = 10.1038/35004614 | bibcode = 2000Natur.404..201L | s2cid = 4345911 }}{{cite journal | vauthors = Chabalier-Taste C, Racca C, Dozier C, Larminat F | title = BRCA1 is regulated by Chk2 in response to spindle damage | journal = Biochim. Biophys. Acta | volume = 1783 | issue = 12 | pages = 2223–33 | date = December 2008 | pmid = 18804494 | doi = 10.1016/j.bbamcr.2008.08.006 | doi-access = free }} [209] => * [[CLSPN]]{{cite journal | vauthors = Lin SY, Li K, Stewart GS, Elledge SJ | title = Human Claspin works with BRCA1 to both positively and negatively regulate cell proliferation | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 101 | issue = 17 | pages = 6484–9 | date = April 2004 | pmid = 15096610 | pmc = 404071 | doi = 10.1073/pnas.0401847101 | bibcode = 2004PNAS..101.6484L | doi-access = free }} [210] => * [[Cofactor of BRCA1|COBRA1]]{{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 = J. Cell Biol. | volume = 155 | issue = 6 | pages = 911–21 | date = December 2001 | pmid = 11739404 | pmc = 2150890 | doi = 10.1083/jcb.200108049 }} [211] => * [[CREB-binding protein|CREBBP]]{{cite journal | vauthors = Benezra M, Chevallier N, Morrison DJ, MacLachlan TK, El-Deiry WS, Licht JD | title = BRCA1 augments transcription by the NF-kappaB transcription factor by binding to the Rel domain of the p65/RelA subunit | journal = J. Biol. Chem. | volume = 278 | issue = 29 | pages = 26333–41 | date = July 2003 | pmid = 12700228 | doi = 10.1074/jbc.M303076200 | doi-access = free }}{{cite journal | vauthors = Pao GM, Janknecht R, Ruffner H, Hunter T, Verma IM | title = CBP/p300 interact with and function as transcriptional coactivators of BRCA1 | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 97 | issue = 3 | pages = 1020–5 | date = February 2000 | pmid = 10655477 | pmc = 15508 | doi = 10.1073/pnas.97.3.1020 | bibcode = 2000PNAS...97.1020P | doi-access = free }}{{cite journal | vauthors = Chai YL, Cui J, Shao N, Shyam E, Reddy P, Rao VN | title = The second BRCT domain of BRCA1 proteins interacts with p53 and stimulates transcription from the p21WAF1/CIP1 promoter | journal = Oncogene | volume = 18 | issue = 1 | pages = 263–8 | date = January 1999 | pmid = 9926942 | doi = 10.1038/sj.onc.1202323 | doi-access = free }}{{cite journal | vauthors = Fan S, Ma YX, Wang C, Yuan RQ, Meng Q, Wang JA, Erdos M, Goldberg ID, Webb P, Kushner PJ, Pestell RG, Rosen EM | title = p300 Modulates the BRCA1 inhibition of estrogen receptor activity | journal = Cancer Res. | volume = 62 | issue = 1 | pages = 141–51 | date = January 2002 | pmid = 11782371 }}{{cite journal | vauthors = Neish AS, Anderson SF, Schlegel BP, Wei W, Parvin JD | title = Factors associated with the mammalian RNA polymerase II holoenzyme | journal = Nucleic Acids Res. | volume = 26 | issue = 3 | pages = 847–53 | date = February 1998 | pmid = 9443979 | pmc = 147327 | doi = 10.1093/nar/26.3.847 }} [212] => * [[CSNK2B]]{{cite journal | vauthors = O'Brien KA, Lemke SJ, Cocke KS, Rao RN, Beckmann RP | title = Casein kinase 2 binds to and phosphorylates BRCA1 | journal = Biochem. Biophys. Res. Commun. | volume = 260 | issue = 3 | pages = 658–64 | date = July 1999 | pmid = 10403822 | doi = 10.1006/bbrc.1999.0892 }} [213] => * [[CSTF2]]{{cite journal | vauthors = Kleiman FE, Manley JL | title = The BARD1-CstF-50 interaction links mRNA 3' end formation to DNA damage and tumor suppression | journal = Cell | volume = 104 | issue = 5 | pages = 743–53 | date = March 2001 | pmid = 11257228 | doi = 10.1016/S0092-8674(01)00270-7 | doi-access = free }}{{cite journal | vauthors = Kleiman FE, Manley JL | title = Functional interaction of BRCA1-associated BARD1 with polyadenylation factor CstF-50 | journal = Science | volume = 285 | issue = 5433 | pages = 1576–9 | date = September 1999 | pmid = 10477523 | doi = 10.1126/science.285.5433.1576 }} [214] => * [[Cyclin-dependent kinase 2|CDK2]]{{cite journal | vauthors = Wang H, Shao N, Ding QM, Cui J, Reddy ES, Rao VN | title = BRCA1 proteins are transported to the nucleus in the absence of serum and splice variants BRCA1a, BRCA1b are tyrosine phosphoproteins that associate with E2F, cyclins and cyclin dependent kinases | journal = Oncogene | volume = 15 | issue = 2 | pages = 143–57 | date = Jul 1997 | pmid = 9244350 | doi = 10.1038/sj.onc.1201252 | doi-access = free }}{{cite journal | vauthors = Chen Y, Farmer AA, Chen CF, Jones DC, Chen PL, Lee WH | title = BRCA1 is a 220-kDa nuclear phosphoprotein that is expressed and phosphorylated in a cell cycle-dependent manner | journal = Cancer Res. | volume = 56 | issue = 14 | pages = 3168–72 | date = July 1996 | pmid = 8764100 }}{{cite journal | vauthors = Ruffner H, Jiang W, Craig AG, Hunter T, Verma IM | title = BRCA1 is phosphorylated at serine 1497 in vivo at a cyclin-dependent kinase 2 phosphorylation site | journal = Mol. Cell. Biol. | volume = 19 | issue = 7 | pages = 4843–54 | date = July 1999 | pmid = 10373534 | pmc = 84283 | doi = 10.1128/MCB.19.7.4843}} [215] => * [[DHX9]]{{cite journal | vauthors = Schlegel BP, Starita LM, Parvin JD | title = Overexpression of a protein fragment of RNA helicase A causes inhibition of endogenous BRCA1 function and defects in ploidy and cytokinesis in mammary epithelial cells | journal = Oncogene | volume = 22 | issue = 7 | pages = 983–91 | date = February 2003 | pmid = 12592385 | doi = 10.1038/sj.onc.1206195 | doi-access = free }}{{cite journal | vauthors = Anderson SF, Schlegel BP, Nakajima T, Wolpin ES, Parvin JD | title = BRCA1 protein is linked to the RNA polymerase II holoenzyme complex via RNA helicase A | journal = Nat. Genet. | volume = 19 | issue = 3 | pages = 254–6 | date = July 1998 | pmid = 9662397 | doi = 10.1038/930 | s2cid = 10953768 }} [216] => * [[ELK4]]{{cite journal | vauthors = Chai Y, Chipitsyna G, Cui J, Liao B, Liu S, Aysola K, Yezdani M, Reddy ES, Rao VN | title = c-Fos oncogene regulator Elk-1 interacts with BRCA1 splice variants BRCA1a/1b and enhances BRCA1a/1b-mediated growth suppression in breast cancer cells | journal = Oncogene | volume = 20 | issue = 11 | pages = 1357–67 | date = March 2001 | pmid = 11313879 | doi = 10.1038/sj.onc.1204256 | doi-access = free }} [217] => * [[EP300]] [218] => * [[Estrogen receptor alpha|ESR1]]{{cite journal | vauthors = Zheng L, Annab LA, Afshari CA, Lee WH, Boyer TG | title = BRCA1 mediates ligand-independent transcriptional repression of the estrogen receptor | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 98 | issue = 17 | pages = 9587–92 | date = August 2001 | pmid = 11493692 | pmc = 55496 | doi = 10.1073/pnas.171174298 | bibcode = 2001PNAS...98.9587Z | doi-access = free }}{{cite journal | vauthors = Fan S, Ma YX, Wang C, Yuan RQ, Meng Q, Wang JA, Erdos M, Goldberg ID, Webb P, Kushner PJ, Pestell RG, Rosen EM | title = Role of direct interaction in BRCA1 inhibition of estrogen receptor activity | journal = Oncogene | volume = 20 | issue = 1 | pages = 77–87 | date = January 2001 | pmid = 11244506 | doi = 10.1038/sj.onc.1204073 | doi-access = free }}{{cite journal | vauthors = Kawai H, Li H, Chun P, Avraham S, Avraham HK | title = Direct interaction between BRCA1 and the estrogen receptor regulates vascular endothelial growth factor (VEGF) transcription and secretion in breast cancer cells | journal = Oncogene | volume = 21 | issue = 50 | pages = 7730–9 | date = October 2002 | pmid = 12400015 | doi = 10.1038/sj.onc.1205971 | doi-access = free }} [219] => * [[FANCA]]{{cite journal | vauthors = Folias A, Matkovic M, Bruun D, Reid S, Hejna J, Grompe M, D'Andrea A, Moses R | title = BRCA1 interacts directly with the Fanconi anemia protein FANCA | journal = Hum. Mol. Genet. | volume = 11 | issue = 21 | pages = 2591–7 | date = October 2002 | pmid = 12354784 | doi = 10.1093/hmg/11.21.2591 | doi-access = free }} [220] => * [[FANCD2]]{{cite journal | vauthors = Reuter TY, Medhurst AL, Waisfisz Q, Zhi Y, Herterich S, Hoehn H, Gross HJ, Joenje H, Hoatlin ME, Mathew CG, Huber PA | title = Yeast two-hybrid screens imply involvement of Fanconi anemia proteins in transcription regulation, cell signaling, oxidative metabolism, and cellular transport | journal = Exp. Cell Res. | volume = 289 | issue = 2 | pages = 211–21 | date = October 2003 | pmid = 14499622 | doi = 10.1016/S0014-4827(03)00261-1 }} [221] => * [[FHL2]]{{cite journal | vauthors = Yan J, Zhu J, Zhong H, Lu Q, Huang C, Ye Q | title = BRCA1 interacts with FHL2 and enhances FHL2 transactivation function | journal = FEBS Lett. | volume = 553 | issue = 1–2 | pages = 183–9 | date = October 2003 | pmid = 14550570 | doi = 10.1016/S0014-5793(03)00978-5 | s2cid = 31566004 | doi-access = free }}{{cite journal | vauthors = Yan JH, Ye QN, Zhu JH, Zhong HJ, Zheng HY, Huang CF | title = [Isolation and characterization of a BRCA1-interacting protein] | language = zh | journal = Yi Chuan Xue Bao | volume = 30 | issue = 12 | pages = 1161–6 | date = December 2003 | pmid = 14986435 }} [222] => * [[H2AFX]]{{cite journal | vauthors = Paull TT, Rogakou EP, Yamazaki V, Kirchgessner CU, Gellert M, Bonner WM | title = A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage | journal = Curr. Biol. | volume = 10 | issue = 15 | pages = 886–95 | year = 2000 | pmid = 10959836 | doi = 10.1016/S0960-9822(00)00610-2 | doi-access = free | bibcode = 2000CBio...10..886P }} [223] => * [[JUNB]] [224] => * [[JunD]]{{cite journal | vauthors = Hu YF, Li R | title = JunB potentiates function of BRCA1 activation domain 1 (AD1) through a coiled-coil-mediated interaction | journal = Genes Dev. | volume = 16 | issue = 12 | pages = 1509–17 | date = June 2002 | pmid = 12080089 | pmc = 186344 | doi = 10.1101/gad.995502 }} [225] => * [[LMO4]]{{cite journal | vauthors = Sutherland KD, Visvader JE, Choong DY, Sum EY, Lindeman GJ, Campbell IG | title = Mutational analysis of the LMO4 gene, encoding a BRCA1-interacting protein, in breast carcinomas | journal = Int. J. Cancer | volume = 107 | issue = 1 | pages = 155–8 | date = October 2003 | pmid = 12925972 | doi = 10.1002/ijc.11343 | s2cid = 20908722 | doi-access = free }}{{cite journal | vauthors = Sum EY, Peng B, Yu X, Chen J, Byrne J, Lindeman GJ, Visvader JE | title = The LIM domain protein LMO4 interacts with the cofactor CtIP and the tumor suppressor BRCA1 and inhibits BRCA1 activity | journal = J. Biol. Chem. | volume = 277 | issue = 10 | pages = 7849–56 | date = March 2002 | pmid = 11751867 | doi = 10.1074/jbc.M110603200 | doi-access = free }} [226] => * [[MAP3K3]]{{cite journal | vauthors = Gilmore PM, McCabe N, Quinn JE, Kennedy RD, Gorski JJ, Andrews HN, McWilliams S, Carty M, Mullan PB, Duprex WP, Liu ET, Johnston PG, Harkin DP | title = BRCA1 interacts with and is required for paclitaxel-induced activation of mitogen-activated protein kinase kinase kinase 3 | journal = Cancer Res. | volume = 64 | issue = 12 | pages = 4148–54 | date = June 2004 | pmid = 15205325 | doi = 10.1158/0008-5472.CAN-03-4080 | doi-access = free }} [227] => * [[MED1]]{{cite journal | vauthors = Wada O, Oishi H, Takada I, Yanagisawa J, Yano T, Kato S | title = BRCA1 function mediates a TRAP/DRIP complex through direct interaction with TRAP220 | journal = Oncogene | volume = 23 | issue = 35 | pages = 6000–5 | date = August 2004 | pmid = 15208681 | doi = 10.1038/sj.onc.1207786 | doi-access = free }} [228] => * [[MED17]]{{cite journal | vauthors = Chiba N, Parvin JD | title = Redistribution of BRCA1 among four different protein complexes following replication blockage | journal = J. Biol. Chem. | volume = 276 | issue = 42 | pages = 38549–54 | date = October 2001 | pmid = 11504724 | doi = 10.1074/jbc.M105227200 | doi-access = free }}{{cite journal | vauthors = Chiba N, Parvin JD | title = The BRCA1 and BARD1 association with the RNA polymerase II holoenzyme | journal = Cancer Res. | volume = 62 | issue = 15 | pages = 4222–8 | date = August 2002 | pmid = 12154023 }} [229] => * [[MED21]]{{cite journal | vauthors = Scully R, Anderson SF, Chao DM, Wei W, Ye L, Young RA, Livingston DM, Parvin JD | title = BRCA1 is a component of the RNA polymerase II holoenzyme | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 94 | issue = 11 | pages = 5605–10 | date = May 1997 | pmid = 9159119 | pmc = 20825 | doi = 10.1073/pnas.94.11.5605 | bibcode = 1997PNAS...94.5605S | doi-access = free }} [230] => * [[MED24]] [231] => * [[MRE11A]]{{cite journal | vauthors = Paull TT, Cortez D, Bowers B, Elledge SJ, Gellert M | title = Direct DNA binding by Brca1 | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 98 | issue = 11 | pages = 6086–91 | date = May 2001 | pmid = 11353843 | pmc = 33426 | doi = 10.1073/pnas.111125998 | doi-access = free }} [232] => * [[MSH2]]{{cite journal | vauthors = Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J | title = BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures | journal = Genes Dev. | volume = 14 | issue = 8 | pages = 927–39 | date = April 2000 | pmid = 10783165 | pmc = 316544 | doi = 10.1101/gad.14.8.927}} [233] => * [[MSH3]]{{cite journal | vauthors = Rodriguez M, Yu X, Chen J, Songyang Z | title = Phosphopeptide binding specificities of BRCA1 COOH-terminal (BRCT) domains | journal = J. Biol. Chem. | volume = 278 | issue = 52 | pages = 52914–8 | date = December 2003 | pmid = 14578343 | doi = 10.1074/jbc.C300407200 | doi-access = free }} [234] => * [[MSH6]] [235] => * [[Myc]]{{cite journal | vauthors = Xiong J, Fan S, Meng Q, Schramm L, Wang C, Bouzahza B, Zhou J, Zafonte B, Goldberg ID, Haddad BR, Pestell RG, Rosen EM | title = BRCA1 inhibition of telomerase activity in cultured cells | journal = Mol. Cell. Biol. | volume = 23 | issue = 23 | pages = 8668–90 | date = December 2003 | pmid = 14612409 | pmc = 262673 | doi = 10.1128/MCB.23.23.8668-8690.2003 }}{{cite journal | vauthors = Zhou C, Liu J | title = Inhibition of human telomerase reverse transcriptase gene expression by BRCA1 in human ovarian cancer cells | journal = Biochem. Biophys. Res. Commun. | volume = 303 | issue = 1 | pages = 130–6 | date = March 2003 | pmid = 12646176 | doi = 10.1016/S0006-291X(03)00318-8 }} [236] => * [[Nibrin|NBN]] [237] => * [[N-myc-interactor|NMI]]{{cite journal | vauthors = Li H, Lee TH, Avraham H | title = A novel tricomplex of BRCA1, Nmi, and c-Myc inhibits c-Myc-induced human telomerase reverse transcriptase gene (hTERT) promoter activity in breast cancer | journal = J. Biol. Chem. | volume = 277 | issue = 23 | pages = 20965–73 | date = June 2002 | pmid = 11916966 | doi = 10.1074/jbc.M112231200 | doi-access = free }} [238] => * [[NPM1]] [239] => * [[Nuclear receptor coactivator 2|NCOA2]]{{cite journal | vauthors = Park JJ, Irvine RA, Buchanan G, Koh SS, Park JM, Tilley WD, Stallcup MR, Press MF, Coetzee GA | title = Breast cancer susceptibility gene 1 (BRCAI) is a coactivator of the androgen receptor | journal = Cancer Res. | volume = 60 | issue = 21 | pages = 5946–9 | date = November 2000 | pmid = 11085509 }} [240] => * [[NUFIP1]]{{cite journal | vauthors = Cabart P, Chew HK, Murphy S | title = BRCA1 cooperates with NUFIP and P-TEFb to activate transcription by RNA polymerase II | journal = Oncogene | volume = 23 | issue = 31 | pages = 5316–29 | date = July 2004 | pmid = 15107825 | doi = 10.1038/sj.onc.1207684 | doi-access = free }} [241] => * [[P53]]{{cite journal | vauthors = Abramovitch S, Werner H | title = Functional and physical interactions between BRCA1 and p53 in transcriptional regulation of the IGF-IR gene | journal = Horm. Metab. Res. | volume = 35 | issue = 11–12 | pages = 758–62 | year = 2003 | pmid = 14710355 | doi = 10.1055/s-2004-814154 | s2cid = 20898175 }}{{cite journal | vauthors = Ouchi T, Monteiro AN, August A, Aaronson SA, Hanafusa H | title = BRCA1 regulates p53-dependent gene expression | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 95 | issue = 5 | pages = 2302–6 | date = March 1998 | pmid = 9482880 | pmc = 19327 | doi = 10.1073/pnas.95.5.2302 | bibcode = 1998PNAS...95.2302O | doi-access = free }}{{cite journal | vauthors = Zhang H, Somasundaram K, Peng Y, Tian H, Zhang H, Bi D, Weber BL, El-Deiry WS | title = BRCA1 physically associates with p53 and stimulates its transcriptional activity | journal = Oncogene | volume = 16 | issue = 13 | pages = 1713–21 | date = April 1998 | pmid = 9582019 | doi = 10.1038/sj.onc.1201932 | doi-access = free }} [242] => * [[PALB2]]{{cite journal | vauthors = Sy SM, Huen MS, Chen J | title = PALB2 is an integral component of the BRCA complex required for homologous recombination repair | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 106 | issue = 17 | pages = 7155–60 | date = April 2009 | pmid = 19369211 | pmc = 2678481 | doi = 10.1073/pnas.0811159106 | bibcode = 2009PNAS..106.7155S | doi-access = free }} [243] => * [[POLR2A]]{{cite journal | vauthors = Krum SA, Miranda GA, Lin C, Lane TF | title = BRCA1 associates with processive RNA polymerase II | journal = J. Biol. Chem. | volume = 278 | issue = 52 | pages = 52012–20 | date = December 2003 | pmid = 14506230 | doi = 10.1074/jbc.M308418200 | doi-access = free }}{{cite journal | vauthors = Krum SA, Womack JE, Lane TF | title = Bovine BRCA1 shows classic responses to genotoxic stress but low in vitro transcriptional activation activity | journal = Oncogene | volume = 22 | issue = 38 | pages = 6032–44 | date = September 2003 | pmid = 12955082 | doi = 10.1038/sj.onc.1206515 | doi-access = free }} [244] => * [[PPP1CA]]{{cite journal | vauthors = Liu Y, Virshup DM, White RL, Hsu LC | title = Regulation of BRCA1 phosphorylation by interaction with protein phosphatase 1alpha | journal = Cancer Res. | volume = 62 | issue = 22 | pages = 6357–61 | date = November 2002 | pmid = 12438214 }} [245] => * [[Rad50]]{{cite journal | vauthors = Zhong Q, Chen CF, Li S, Chen Y, Wang CC, Xiao J, Chen PL, Sharp ZD, Lee WH | title = Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA damage response | journal = Science | volume = 285 | issue = 5428 | pages = 747–50 | date = July 1999 | pmid = 10426999 | doi = 10.1126/science.285.5428.747 }} [246] => * [[RAD51]]{{cite journal | vauthors = Chen J, Silver DP, Walpita D, Cantor SB, Gazdar AF, Tomlinson G, Couch FJ, Weber BL, Ashley T, Livingston DM, Scully R | title = Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells | journal = Mol. Cell | volume = 2 | issue = 3 | pages = 317–28 | date = September 1998 | pmid = 9774970 | doi = 10.1016/S1097-2765(00)80276-2 | doi-access = free }}{{cite journal | vauthors = Scully R, Chen J, Plug A, Xiao Y, Weaver D, Feunteun J, Ashley T, Livingston DM | title = Association of BRCA1 with Rad51 in mitotic and meiotic cells | journal = Cell | volume = 88 | issue = 2 | pages = 265–75 | date = January 1997 | pmid = 9008167 | doi = 10.1016/S0092-8674(00)81847-4 | doi-access = free }} [247] => * [[RBBP4]] [248] => * [[RBBP7]]{{cite journal | vauthors = Yarden RI, Brody LC | title = BRCA1 interacts with components of the histone deacetylase complex | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 96 | issue = 9 | pages = 4983–8 | date = April 1999 | pmid = 10220405 | pmc = 21803 | doi = 10.1073/pnas.96.9.4983 | bibcode = 1999PNAS...96.4983Y | doi-access = free }}{{cite journal | vauthors = Chen GC, Guan LS, Yu JH, Li GC, Choi Kim HR, Wang ZY | title = Rb-associated protein 46 (RbAp46) inhibits transcriptional transactivation mediated by BRCA1 | journal = Biochem. Biophys. Res. Commun. | volume = 284 | issue = 2 | pages = 507–14 | date = June 2001 | pmid = 11394910 | doi = 10.1006/bbrc.2001.5003 }}{{cite journal | vauthors = Yarden RI, Brody LC | title = Identification of proteins that interact with BRCA1 by Far-Western library screening | journal = J. Cell. Biochem. | volume = 83 | issue = 4 | pages = 521–31 | year = 2001 | pmid = 11746496 | doi = 10.1002/jcb.1257 | s2cid = 29703139 | url = https://zenodo.org/record/1229223 }} [249] => * [[RBBP8]]{{cite journal | vauthors = Yu X, Wu LC, Bowcock AM, Aronheim A, Baer R | title = The C-terminal (BRCT) domains of BRCA1 interact in vivo with CtIP, a protein implicated in the CtBP pathway of transcriptional repression | journal = J. Biol. Chem. | volume = 273 | issue = 39 | pages = 25388–92 | date = September 1998 | pmid = 9738006 | doi = 10.1074/jbc.273.39.25388 | doi-access = free }}{{cite journal | vauthors = Li S, Chen PL, Subramanian T, Chinnadurai G, Tomlinson G, Osborne CK, Sharp ZD, Lee WH | title = Binding of CtIP to the BRCT repeats of BRCA1 involved in the transcription regulation of p21 is disrupted upon DNA damage | journal = J. Biol. Chem. | volume = 274 | issue = 16 | pages = 11334–8 | date = April 1999 | pmid = 10196224 | doi = 10.1074/jbc.274.16.11334 | doi-access = free }}{{cite journal | vauthors = Wong AK, Ormonde PA, Pero R, Chen Y, Lian L, Salada G, Berry S, Lawrence Q, Dayananth P, Ha P, Tavtigian SV, Teng DH, Bartel PL | title = Characterization of a carboxy-terminal BRCA1 interacting protein | journal = Oncogene | volume = 17 | issue = 18 | pages = 2279–85 | date = November 1998 | pmid = 9811458 | doi = 10.1038/sj.onc.1202150 | doi-access = free }}{{cite journal | vauthors = Li S, Ting NS, Zheng L, Chen PL, Ziv Y, Shiloh Y, Lee EY, Lee WH |author7-link=Eva Y.-H. P. Lee | title = Functional link of BRCA1 and ataxia telangiectasia gene product in DNA damage response | journal = Nature | volume = 406 | issue = 6792 | pages = 210–5 | date = July 2000 | pmid = 10910365 | doi = 10.1038/35018134 | bibcode = 2000Natur.406..210L | s2cid = 3266654 }}{{cite journal | vauthors = Wu-Baer F, Baer R | title = Effect of DNA damage on a BRCA1 complex | journal = Nature | volume = 414 | issue = 6859 | page = 36 | date = November 2001 | pmid = 11689934 | doi = 10.1038/35102118 | s2cid = 4329675 | doi-access = free }}{{cite journal | vauthors = Yu X, Baer R | title = Nuclear localization and cell cycle-specific expression of CtIP, a protein that associates with the BRCA1 tumor suppressor | journal = J. Biol. Chem. | volume = 275 | issue = 24 | pages = 18541–9 | date = June 2000 | pmid = 10764811 | doi = 10.1074/jbc.M909494199 | doi-access = free }} [250] => * [[RELA]] [251] => * [[Retinoblastoma protein|RB1]]{{cite journal | vauthors = Aprelikova ON, Fang BS, Meissner EG, Cotter S, Campbell M, Kuthiala A, Bessho M, Jensen RA, Liu ET | title = BRCA1-associated growth arrest is RB-dependent | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 96 | issue = 21 | pages = 11866–71 | date = October 1999 | pmid = 10518542 | pmc = 18378 | doi = 10.1073/pnas.96.21.11866 | bibcode = 1999PNAS...9611866A | doi-access = free }} [252] => * [[Retinoblastoma-like protein 1|RBL1]] [253] => * [[Retinoblastoma-like protein 2|RBL2]]{{cite journal | vauthors = Fan S, Yuan R, Ma YX, Xiong J, Meng Q, Erdos M, Zhao JN, Goldberg ID, Pestell RG, Rosen EM | title = Disruption of BRCA1 LXCXE motif alters BRCA1 functional activity and regulation of RB family but not RB protein binding | journal = Oncogene | volume = 20 | issue = 35 | pages = 4827–41 | date = August 2001 | pmid = 11521194 | doi = 10.1038/sj.onc.1204666 | doi-access = free }} [254] => * [[RPL31]] [255] => * [[SMARCA4]]{{cite journal | vauthors = Hill DA, de la Serna IL, Veal TM, Imbalzano AN | title = BRCA1 interacts with dominant negative SWI/SNF enzymes without affecting homologous recombination or radiation-induced gene activation of p21 or Mdm2 | journal = J. Cell. Biochem. | volume = 91 | issue = 5 | pages = 987–98 | date = April 2004 | pmid = 15034933 | doi = 10.1002/jcb.20003 | s2cid = 40668596 | doi-access = free }} [256] => * [[SMARCB1]]{{cite journal | vauthors = Bochar DA, Wang L, Beniya H, Kinev A, Xue Y, Lane WS, Wang W, Kashanchi F, Shiekhattar R | title = BRCA1 is associated with a human SWI/SNF-related complex: linking chromatin remodeling to breast cancer | journal = Cell | volume = 102 | issue = 2 | pages = 257–65 | date = July 2000 | pmid = 10943845 | doi = 10.1016/S0092-8674(00)00030-1 | doi-access = free }} [257] => * [[STAT1]]{{cite journal | vauthors = Ouchi T, Lee SW, Ouchi M, Aaronson SA, Horvath CM | title = Collaboration of signal transducer and activator of transcription 1 (STAT1) and BRCA1 in differential regulation of IFN-gamma target genes | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 97 | issue = 10 | pages = 5208–13 | date = May 2000 | pmid = 10792030 | pmc = 25807 | doi = 10.1073/pnas.080469697 | bibcode = 2000PNAS...97.5208O | doi-access = free }} [258] => * [[TOPBP1]]{{cite book |vauthors=Sokka M, Parkkinen S, Pospiech H, Syvaoja JE |chapter=Function of TopBP1 in Genome Stability |veditors=Nasheuer HP |title=Genome Stability and Human Diseases |series=Subcellular Biochemistry |publisher=Springer Dordrecht | pages = 119–141 | date = April 2012 |volume=50 | doi = 10.1007/978-90-481-3471-7_7 |pmid=20012580 |isbn=978-90-481-3471-7}} [259] => * [[UBE2D1]]{{cite journal | vauthors = Mallery DL, Vandenberg CJ, Hiom K | title = Activation of the E3 ligase function of the BRCA1/BARD1 complex by polyubiquitin chains | journal = EMBO J. | volume = 21 | issue = 24 | pages = 6755–62 | date = December 2002 | pmid = 12485996 | pmc = 139111 | doi = 10.1093/emboj/cdf691 }}{{cite journal | vauthors = Brzovic PS, Keeffe JR, Nishikawa H, Miyamoto K, Fox D, Fukuda M, Ohta T, Klevit R | title = Binding and recognition in the assembly of an active BRCA1/BARD1 ubiquitin-ligase complex | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 100 | issue = 10 | pages = 5646–51 | date = May 2003 | pmid = 12732733 | pmc = 156255 | doi = 10.1073/pnas.0836054100 | bibcode = 2003PNAS..100.5646B | doi-access = free }}{{cite journal | vauthors = Nishikawa H, Ooka S, Sato K, Arima K, Okamoto J, Klevit RE, Fukuda M, Ohta T | title = Mass spectrometric and mutational analyses reveal Lys-6-linked polyubiquitin chains catalyzed by BRCA1-BARD1 ubiquitin ligase | journal = J. Biol. Chem. | volume = 279 | issue = 6 | pages = 3916–24 | date = February 2004 | pmid = 14638690 | doi = 10.1074/jbc.M308540200 | doi-access = free }}{{cite journal | vauthors = Kentsis A, Gordon RE, Borden KL | title = Control of biochemical reactions through supramolecular RING domain self-assembly | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 99 | issue = 24 | pages = 15404–9 | date = November 2002 | pmid = 12438698 | pmc = 137729 | doi = 10.1073/pnas.202608799 | bibcode = 2002PNAS...9915404K | doi-access = free }}{{cite journal | vauthors = Chen A, Kleiman FE, Manley JL, Ouchi T, Pan ZQ | title = Autoubiquitination of the BRCA1*BARD1 RING ubiquitin ligase | journal = J. Biol. Chem. | volume = 277 | issue = 24 | pages = 22085–92 | date = June 2002 | pmid = 11927591 | doi = 10.1074/jbc.M201252200 | doi-access = free }}{{cite journal | vauthors = Dong Y, Hakimi MA, Chen X, Kumaraswamy E, Cooch NS, Godwin AK, Shiekhattar R | title = Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair | journal = Mol. Cell | volume = 12 | issue = 5 | pages = 1087–99 | date = November 2003 | pmid = 14636569 | doi = 10.1016/S1097-2765(03)00424-6 | doi-access = free }}{{cite journal | vauthors = Sato K, Hayami R, Wu W, Nishikawa T, Nishikawa H, Okuda Y, Ogata H, Fukuda M, Ohta T | title = Nucleophosmin/B23 is a candidate substrate for the BRCA1-BARD1 ubiquitin ligase | journal = J. Biol. Chem. | volume = 279 | issue = 30 | pages = 30919–22 | date = July 2004 | pmid = 15184379 | doi = 10.1074/jbc.C400169200 | doi-access = free }}{{cite journal | vauthors = Vandenberg CJ, Gergely F, Ong CY, Pace P, Mallery DL, Hiom K, Patel KJ | title = BRCA1-independent ubiquitination of FANCD2 | journal = Mol. Cell | volume = 12 | issue = 1 | pages = 247–54 | date = July 2003 | pmid = 12887909 | doi = 10.1016/S1097-2765(03)00281-8 | doi-access = free }}{{cite journal | vauthors = Wu-Baer F, Lagrazon K, Yuan W, Baer R | title = The BRCA1/BARD1 heterodimer assembles polyubiquitin chains through an unconventional linkage involving lysine residue K6 of ubiquitin | journal = J. Biol. Chem. | volume = 278 | issue = 37 | pages = 34743–6 | date = September 2003 | pmid = 12890688 | doi = 10.1074/jbc.C300249200 | doi-access = free }}{{cite journal | vauthors = Hashizume R, Fukuda M, Maeda I, Nishikawa H, Oyake D, Yabuki Y, Ogata H, Ohta T | title = The RING heterodimer BRCA1-BARD1 is a ubiquitin ligase inactivated by a breast cancer-derived mutation | journal = J. Biol. Chem. | volume = 276 | issue = 18 | pages = 14537–40 | date = May 2001 | pmid = 11278247 | doi = 10.1074/jbc.C000881200 | doi-access = free }} [260] => * [[USF2]]{{cite journal | vauthors = Cable PL, Wilson CA, Calzone FJ, Rauscher FJ, Scully R, Livingston DM, Li L, Blackwell CB, Futreal PA, Afshari CA | title = Novel consensus DNA-binding sequence for BRCA1 protein complexes | journal = Mol. Carcinog. | volume = 38 | issue = 2 | pages = 85–96 | date = October 2003 | pmid = 14502648 | doi = 10.1002/mc.10148 | s2cid = 24956554 | url = https://zenodo.org/record/1229285 }} [261] => * [[Valosin-containing protein|VCP]]{{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 = 253–63 | date = May 2000 | pmid = 10855792 | doi = 10.1089/10445490050021168 }} [262] => * [[XIST (gene)|XIST]]{{cite journal | vauthors = Ganesan S, Silver DP, Drapkin R, Greenberg R, Feunteun J, Livingston DM | title = Association of BRCA1 with the inactive X chromosome and XIST RNA | journal = Philos. Trans. R. Soc. Lond. B Biol. Sci. | volume = 359 | issue = 1441 | pages = 123–8 | date = January 2004 | pmid = 15065664 | pmc = 1693294 | doi = 10.1098/rstb.2003.1371 }}{{cite journal | vauthors = Ganesan S, Silver DP, Greenberg RA, Avni D, Drapkin R, Miron A, Mok SC, Randrianarison V, Brodie S, Salstrom J, Rasmussen TP, Klimke A, Marrese C, Marahrens Y, Deng CX, Feunteun J, Livingston DM | title = BRCA1 supports XIST RNA concentration on the inactive X chromosome | journal = Cell | volume = 111 | issue = 3 | pages = 393–405 | date = November 2002 | pmid = 12419249 | doi = 10.1016/S0092-8674(02)01052-8 | doi-access = free }} [263] => * [[ZNF350]]{{cite journal | vauthors = Zheng L, Pan H, Li S, Flesken-Nikitin A, Chen PL, Boyer TG, Lee WH | title = Sequence-specific transcriptional corepressor function for BRCA1 through a novel zinc finger protein, ZBRK1 | journal = Mol. Cell | volume = 6 | issue = 4 | pages = 757–68 | date = October 2000 | pmid = 11090615 | doi = 10.1016/S1097-2765(00)00075-7 | doi-access = free }} [264] => {{Div col end}} [265] => [266] => ==References== [267] => {{reflist|30em}} [268] => [269] => ==External links== [270] => {{Commons category|BRCA1}} [271] => * {{MeshName|BRCA1+Protein|3=BRCA1 Protein}} [272] => * {{MeshName|Genes,+BRCA1|3=Genes, BRCA1}} [273] => * [https://www.ebi.ac.uk/pdbe/pdbe-kb/proteins/P38398 PDBe-KB] provides an overview of all the structure information available in the PDB for Human BRCA1. [274] => [275] => {{PDB Gallery|geneid=672}} [276] => {{Tumor suppressor genes}} [277] => {{Medicine}} [278] => [279] => [[Category:Breast cancer]] [280] => [[Category:Genes on human chromosome 17]] [281] => [[Category:DNA repair]] [282] => [[Category:Tumor markers]] [283] => [[Category:Tumor suppressor genes]] [] => )
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BRCA1

BRCA1, an abbreviation for Breast Cancer gene 1, is a human gene that produces a protein called breast cancer type 1 susceptibility protein. Mutations in this gene have been linked to an increased risk of developing hereditary breast and ovarian cancer.

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Mutations in this gene have been linked to an increased risk of developing hereditary breast and ovarian cancer. The BRCA1 gene is located on chromosome 17 and plays a crucial role in maintaining the stability of the genome. It is involved in DNA repair, cell division, and the suppression of tumor growth. The presence of specific harmful mutations in BRCA1 can significantly raise the likelihood of developing breast and ovarian cancer. Genetic testing for BRCA1 mutations is available and can help individuals assess their risk. Management options for individuals with BRCA1 mutations include increased surveillance and preventive measures such as prophylactic surgeries or chemoprevention. Research on BRCA1 continues to advance our understanding of the genetic basis of cancer and inform medical interventions.

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