WikiGenes - BRCA1 - breast cancer 1, early onset

Tibbetts, R.S., Lee, J.S., Welcsh, P.L., Franchitto, A., Yarden, R.I., et al.

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Disease relevance of BRCA1

Inheritance of a mutation in the gene BRCA1 confers on women a 50-85% lifetime risk of developing breast cancer [1].
Germline mutations in the tumor suppressor gene, BRCA1, predispose individuals to breast and ovarian cancers [2].
However, this variant is present in 5.1% of individuals with breast cancer from 718 families that do not carry mutations in BRCA1 or BRCA2 (P = 0.00000003), including 13.5% of individuals from families with male breast cancer (P = 0.00015) [3].
The BRIP1 helicase functions independently of BRCA1 in the Fanconi anemia pathway for DNA crosslink repair [4].
Functional link of BRCA1 and ataxia telangiectasia gene product in DNA damage response [5].

Psychiatry related information on BRCA1

The purpose of this report is to review the current state of knowledge of BRCA1 and BRCA2, the biology of associated tumors, and possible risk reduction strategies in women with these deleterious mutations [6].
In contrast to the results with the micronucleus assay, we found no significant individual difference between women with and without a BRCA1 mutation with respect to the induction and repair of DNA damage in the alkaline comet assay [7].
BRCA1 and BRCA2 gene mutations: decision-making dilemmas concerning testing and management [8].
At follow-up, noncarriers of BRCA1 mutations showed statistically significant reductions in depressive symptoms and functional impairment compared with carriers and nontested individuals [9].
The goals of the present study were to describe rates of completing a psychosocial telephone counseling (PTC) intervention that was offered to female BRCA1/2 mutation carriers and to identify sociodemographic and psychological factors associated with decisions to complete the intervention [10].

High impact information on BRCA1

The significant risk factor for development of ovarian cancer is advancing age, although there is clearly a genetic predisposition--often associated with the BRCA1 and BRCA2 genes--in at least 5% to 10% of all epithelial ovarian cancers [11].
The BRCA1-interacting helicase BRIP1 is deficient in Fanconi anemia [12].
Here we show that the protein defective in individuals with Fanconi anemia belonging to complementation group B is an essential component of the nuclear protein 'core complex' responsible for monoubiquitination of FANCD2, a key event in the DNA-damage response pathway associated with Fanconi anemia and BRCA [13].
Here we show that BRCA1 is essential for activating the Chk1 kinase that regulates DNA damage-induced G2/M arrest [14].
Thus, BRCA1 controls the expression, phosphorylation and cellular localization of Cdc25C and Cdc2/cyclin B kinase-proteins that are crucial for the G2/M transition [14].

Chemical compound and disease context of BRCA1

BRCA1 mutations and estrogen use are risk factors for the development of breast cancer [15].
Loss of coordinated androgen regulation in nonmalignant ovarian epithelial cells with BRCA1/2 mutations and ovarian cancer cells [16].
Cells derived from the ovarian surface epithelium of women undergoing oophorectomy (n = 7) for nonovarian indications or with a germ-line BRCA1 or 2 mutation (n = 9), and from the ascitic fluid of patients with primary ovarian cancer (n = 8) were cultured with and without DHT [16].
Polyglutamine repeat length in the AIB1 gene modifies breast cancer susceptibility in BRCA1 carriers [17].
Here, we showed that, in Du-145 human prostate cancer cells, enhanced expression of BRCA1 resulted in constitutive activation of signal transducer and activator transcription factor 3 (STAT3) tyrosine and serine phosphorylation [18].

Biological context of BRCA1

BRCA1 induces DNA damage recognition factors and enhances nucleotide excision repair [1].
We conclude that BRCA1 regulates key effectors that control the G2/M checkpoint and is therefore involved in regulating the onset of mitosis [14].
Using a combination of affinity- and conventional chromatographic techniques, we have isolated a predominant form of a multiprotein BRCA1-containing complex from human cells displaying chromatin-remodeling activity [2].
Although the biochemical function of BRCA1 is not well understood, it is important for DNA damage repair and cell-cycle checkpoint [19].
Mutations in the BRCA1 (ref. 1) tumour suppressor gene are found in almost all of the families with inherited breast and ovarian cancers and about half of the families with only breast cancer [19].

Anatomical context of BRCA1

This phosphorylation is also important for the ability of BRCA1 to restore survival after DNA damage in the BRCA1-mutated cell line HCC1937 [19].
Nearly all BRCA1 germ-line mutations involve truncation or loss of the C-terminal BRCT transcriptional activation domain, suggesting that transcriptional regulation is a critical function of the wild-type gene [20].
We describe a detailed somatic cell hybrid map of human chromosome 17q11.2-q23, containing the familial breast and ovarian cancer locus (BRCA1) and highly informative closely linked markers [21].
Inhibition of BRCA1 expression in mammary epithelial cell lines also suggests that BRCA1 may act as a tumor suppressor [22].
BRCA1 inhibition of telomerase activity in cultured cells [23].

Associations of BRCA1 with chemical compounds

Phosphorylation of BRCA1 at serine 988 is required for the release of BRCA1 from hCds1 [19].
Ectopic expression of wild-type, but not mutated, BRCA1 in these cells rendered them less sensitive to the DNA damage agent, methyl methanesulfonate [24].
In this study, we show that BRCA1 phosphorylation is only partially ATM dependent in response to IR and ATM independent in response to treatment with UV light, or the DNA replication inhibitors hydroxyurea (HU) and aphidicolin (APH) [25].
In this study, we show that BLM function is specifically required to properly relocalize the RAD50/MRE11/NBS1 (RMN) complex at sites of replication arrest, but is not essential in the activation of BRCA1 either after stalled replication forks or gamma-rays [26].
By using UBR60 cells, which carry tetracycline-regulated expression of BRCA1, we demonstrated that BRCA1 binds to transcription factor OCT-1 and up-regulates the transcription of MAD2 [27].

Physical interactions of BRCA1

The FANCD2 protein, therefore, provides the missing link between the FA protein complex and the cellular BRCA1 repair machinery [28].
Binding and recognition in the assembly of an active BRCA1/BARD1 ubiquitin-ligase complex [29].
Significantly, STAT1 proteins mutated at Ser-727 bind poorly to BRCA1, reinforcing the importance of Ser-727 in the recruitment of transcriptional coactivators by STAT proteins [30].
The second BRCT domain of BRCA1 proteins interacts with p53 and stimulates transcription from the p21WAF1/CIP1 promoter [31].
Immunoprecipitation assay showed that BRCA1 interacted with JAK1 and JAK2 [18].

Enzymatic interactions of BRCA1

BRCA1 is phosphorylated at serine 1497 in vivo at a cyclin-dependent kinase 2 phosphorylation site [32].
Brca1 is hyperphosphorylated in response to DNA damage and co-localizes with Rad51, a protein involved in homologous-recombination, and Nbs1.Mre11.Rad50, a complex required for both homologous-recombination and nonhomologous end joining repair of damaged DNA [33].
ATR phosphorylates BRCA1 on six Ser/Thr residues, including Ser 1423, in vitro [25].
We then delineated the biochemical characteristics of the complex and found that BRCA1 interacts solely with the phosphorylated and inactive form of ACCA (P-ACCA) [34].
Here we report the crystal structure of the BRCT repeats of human BRCA1 bound to a phosphorylated BACH1 peptide at 2.3 A resolution [35].

Co-localisations of BRCA1

FANCD2 complexes and colocalizes with BRCA1, but its presumptive role in DNA repair has not yet been clearly defined [36].
A recent report that BRCA1 and human Rad51 colocalize in S-phase cells suggests a role for BRCA1 in DNA damage repair [37].

Regulatory relationships of BRCA1

We now report that the ability of BRCA1 to repress ER-alpha activity correlates with its ability to induce down-regulation of the cellular levels of the transcriptional coactivator p300 in breast and prostate, but not in cervical cancer cells [38].
Ataxia telangiectasia mutated and checkpoint kinase 2 regulate BRCA1 to promote the fidelity of DNA end-joining [39].
In transfected prostate and breast cancer cell lines, BRCA1 enhanced AR-dependent transactivation of a probasin-derived reporter gene [40].
BRCA1-induced apoptosis involves inactivation of ERK1/2 activities [41].
Taken together these data suggest that MDC1 regulates BRCA1 function in DNA damage checkpoint control [42].

Other interactions of BRCA1

Our results indicate that somatic BRCA2 mutations, like somatic mutations in the BRCA1 gene, are very rare in primary breast cancers [43].
Given the suspected role of BRCA1/BARD1 in DNA repair, we tested whether inhibition of mRNA processing is linked to