A Strong Candidate for the Breast and Ovarian Cancer Susceptibility Gene
            <i>BRCA1</i>

Miki, Yoshio; Swensen, Jeff; Shattuck-Eidens, Donna; Futreal, P. Andrew; Harshman, Keith; Tavtigian, Sean V.; Liu, Qingyun; Cochran, Charles; Bennett, Lee; Ding, Wei; Bell, Russell; Rosenthal, Judith; Hussey, Charles E.; Tran, Thanh V.; McClure, Melody; Frye, Cheryl A.; Hattier, Thomas; Phelps, Robert; Haugen‐Strano, Astrid; Katcher, Harold L.; Yakumo, Kazuko; Gholami, Zahra; Shaffer, Daniel J.; Stone, Steven; Bayer, Steven R.; Wray, Christian; Bogden, Robert; Dayananth, Priya; Ward, John H.; Tonin, Patricia N.; Narod, Steven A.; Bristow, Pam K.; Norris, Frank H.; Helvering, Leah M.; Morrison, Paul J.; Rosteck, Paul R.; Lai, Mei‐Huei T.; Barrett, J. Carl; Lewis, Cathryn M.; Neuhausen, Susan L.; Cannon-Albright, Lisa; Goldgar, David E.; Wiseman, Roger W.; Kamb, Alexander; Skolnick, Mark H.

doi:10.1126/science.7545954

Cited by 5,631 publications

(3,410 citation statements)

References 28 publications

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“…The ability of BRCA1 to biochemically modulate p53 function suggests that this may be a fundamental role of BRCA1 in tumor suppression. It is noteworthy that inherited defects of either p53 or BRCA1 can lead to the development of breast cancer in humans (Malkin et al, 1990;Miki et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

“…Susceptibility to early-onset breast and ovarian cancer is conferred by mutations in a gene on chromosome 17q21. This gene, termed BRCA1, has been identi®ed by positional cloning (Miki et al, 1994). Mutations in the BRCA1 gene account for about 50% of inherited breast cancer cases and 80% of families predisposed to both breast and ovarian cancer.…”

Section: Introductionmentioning

confidence: 99%

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BRCA1 physically associates with p53 and stimulates its transcriptional activity

et al. 1998

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Mutations of the BRCA1 tumor suppressor gene are the most commonly detected alterations in familial breast and ovarian cancer. Although BRCA1 is required for normal mouse development, the molecular basis for its tumor suppressive function remains poorly understood. We show here that BRCA1 increases p53-dependent transcription from the p21 WAF1/CIP1 and bax promoters. We also show that BRCA1 and p53 proteins interact both in vitro and in vivo. The interacting regions map, in vitro, to aa 224 ± 500 of BRCA1 and the C-terminal domain of p53. Tumor-derived transactivation-de®cient BRCA1 mutants are defective in co-activation of p53-dependent transcription and a truncation mutant of BRCA1 that retains the p53-interacting region acts as a dominant inhibitor of p53-dependent transcription. BRCA1 and p53 cooperatively induce apoptosis of cancer cells. The results indicate that BRCA1 and p53 may coordinately regulate gene expression in their role as tumor suppressors.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

BRCA1 physically associates with p53 and stimulates its transcriptional activity

et al. 1998

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“…Familial breast cancer (FBC) includes tumors from patients carrying mutations in the two known breast cancer susceptibility genes: BRCA1 (Miki et al, 1994) and BRCA2 (Wooster et al, 1995). However, most of FBC patients do not carry mutations in these genes, and are known as non-BRCA1/2 or BRCAX cases.…”

Section: Introductionmentioning

confidence: 99%

Distinct genomic aberration patterns are found in familial breast cancer associated with different immunohistochemical subtypes

et al. 2007

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Five breast cancer subtypes have been described in sporadic breast cancer (SBC) using expression arrays: basal-like, ERBB2, normal breast-like, luminal A and B. These molecular subtypes show different genomic aberration patterns (GAPs). Recently, our group described these breast cancer subtypes in 50 non-BRCA1/2 familial tumors using immunohistochemistry assays. We extended this study to the other classes of familial breast cancer (FBC), including 62 tumors (18 BRCA1, 16 BRCA2 and 28 non-BRCA1/2), with the same panel of 25 immunohistochemical (IHC) markers and histological grade obtaining a similar classification. We combined these data with results generated by a 1 Mb BAC array-based CGH study to evaluate the genomic aberrations of each group. We found that BRCA1-related tumors are preferentially basal-like, whereas non-BRCA1/2 familial tumors are mainly luminal A subtype. We described distinct GAPs related to each IHC subtype. Basal tumors had a greater number of gains/losses, while luminal B tumors had more high-level DNA amplifications. Our data are similar to those obtained in SBC studies, highlighting the existence of distinct genetic pathways of tumor evolution, common to both SBC and FBC.

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“…Because BRCA1 is expressed at higher levels in the breast and ovary than in most other tissues/organs (Miki et al, 1994;Lane et al, 1995), it is conceivable that BRCA1 does not have an indispensable role in other tissues, where it is expressed at low levels. DNA damage triggered by BRCA1 deficiency in these tissues can be repaired efficiently by other proteins performing the similar function as BRCA1, whereas in mammary and ovarian tissues, these other proteins may not be expressed at adequate levels to conduct efficient repairing.…”

Section: Introductionmentioning

confidence: 99%

A role of estrogen/ERα signaling in BRCA1-associated tissue-specific tumor formation

Xiao

et al. 2007

Oncogene

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Estrogen and its receptor alpha (ERa) have been implicated in the tissue-specific tumorigenesis associated with BRCA1 mutations. However, the majority of breast cancers developed in human BRCA1 mutation carriers are ERa-negative, challenging the link between BRCA1 and estrogen/ERa in breast cancer formation. Using a mouse model lacking the full-length form of BRCA1, here we show that ERa is highly expressed in the premalignant mammary gland and initiation stages of tumorigenesis, although its expression is gradually diminished during mammary tumor progression. We demonstrate that the absence of full-length BRCA1 increases sensitivity of cells to estrogen-induced extracellular signal-regulated kinase 1/2 phosphorylation and cyclin D1 expression. The absence of BRCA1 turns the proliferation of ERa-positive cells from a paracrine fashion to an autocrine or endocrine fashion. Consequently, BRCA1-mutant cells are sensitized to estrogen-induced cell proliferation in vitro and mammary tumorigenesis in vivo. These findings illustrate a molecular mechanism for estrogen/ERa signals in BRCA1-associated tissue-specific tumor formation, and identify several key elements in the estrogen/ERasignaling cascade that can serve as potential therapeutic targets for BRCA1-associated tumorigenesis.

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A Strong Candidate for the Breast and Ovarian Cancer Susceptibility Gene BRCA1

Cited by 5,631 publications

References 28 publications

BRCA1 physically associates with p53 and stimulates its transcriptional activity

BRCA1 physically associates with p53 and stimulates its transcriptional activity

Distinct genomic aberration patterns are found in familial breast cancer associated with different immunohistochemical subtypes

A role of estrogen/ERα signaling in BRCA1-associated tissue-specific tumor formation

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