Mammary tumors in mice conditionally mutant for Brca1 exhibit gross genomic instability and centrosome amplification yet display a recurring distribution of genomic imbalances that is similar to human breast cancer

Weaver, Zoë; Montagna, Cristina; Xu, Xiaoling; Howard, Tamara; Gadina, Massimo; Brodie, Steven G.; Deng, Chu Xia; Ried, Thomas

doi:10.1038/sj.onc.1205636

Cited by 131 publications

(119 citation statements)

References 30 publications

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“…This role has been confirmed in experiments in which embryonic fibroblasts derived from wild-type BRCA1-deficient mice showed amplified centrosome numbers. Centrosomal amplification is known to be a hallmark of cells whose BRCA1 expression or function has been disrupted (Weaver et al, 2002;Birgisdottir et al, 2006;Chen et al, 2006). Interestingly, we observed a similar phenomenon of centrosomal amplification in MTA1 overexpressing cells (Figure 6b).…”

Section: Discussionsupporting

confidence: 70%

“…Studies have shown that BRCA1 localizes to the centrosome and binds to g-tubulin, a major component of centrosomes (Starita et al, 2004). In addition, BRCA1 has been shown to interact with a variety of proteins that regulate centrosome duplication like BRCA2, BubR1, CDK2-cyclin A, CDK2-cyclin E, Gadd45, p21, p53 and Rb) (Weaver et al, 2002;Chabalier et al, 2006). This role has been confirmed in experiments in which embryonic fibroblasts derived from wild-type BRCA1-deficient mice showed amplified centrosome numbers.…”

Section: Discussionmentioning

confidence: 99%

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MTA1-mediated transcriptional repression of BRCA1 tumor suppressor gene

et al. 2007

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Metastasis-associated tumor antigen 1 (MTA1), a component of the nucleosome remodeling and deacetylating (NuRD) complex is routinely upregulated in several cancers. In the present study, we investigated the potential role of MTA1 in BRCA1 transcriptional repression and subsequent chromosomal instability. MTA1-NuRD complex was found to negatively regulate BRCA1 transcription by physically associating with an atypical estrogen-responsive element (ERE) on the BRCA1 promoter. Moreover, MTA1 and HDAC complex recruited to the ERE of BRCA1 promoter in an ER a-dependent manner. Accordingly, BRCA1 protein levels were enhanced by silencing of either MTA1 expression or by treatment with the specific histone deacetylase inhibitor trichostatin A. MTA1's strong repressive effects on BRCA1 expression was supported by our observation that cells stably overexpressing MTA1 showed centrosome amplification which has been long implicated as a phenotype for BRCA1 repression. Accordingly, overexpression of BRCA1 in cells stably over expressing MTA1 resulted in restoration of normal centrosome numbers. Together, these findings strongly implicate MTA1 in the transcriptional repression of BRCA1 leading to abnormal centrosome number and chromosomal instability.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

MTA1-mediated transcriptional repression of BRCA1 tumor suppressor gene

et al. 2007

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“…Interestingly, the pattern of chromosomal rearrangements in the mouse tumors resembled those found in human BRCA1 mutant cancers (Weaver et al, 2002). Cultured tumor cells were resistant to the anti-estrogen Tamoxifen but were very sensitive to the DNA damaging agents adriamycin and ionizing radiation.…”

Section: Brca1 Regulation Of the Proteomementioning

confidence: 83%

BRCA1 gene in breast cancer

Rosen

Fan

Pestell

et al. 2003

Journal Cellular Physiology

237

195

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The BRCA1 gene was identified and cloned in 1994 based on its linkage to early onset breast cancer and breast-ovarian cancer syndromes in women. While inherited mutations of BRCA1 are responsible for about 40-45% of hereditary breast cancers, these mutations account for only 2-3% of all breast cancers, since the BRCA1 gene is rarely mutated in sporadic breast cancers. However, BRCA1 expression is frequently reduced or absent in sporadic cancers, suggesting a much wider role in mammary carcinogenesis. Since BRCA1 was cloned in 1994, its molecular function has been the subject of intense investigation. These studies have revealed multiple functions of the BRCA1 that may contribute to its tumor suppressor activity, including roles in: cell cycle progression, several highly specialized DNA repair processes, DNA damage-responsive cell cycle checkpoints, regulation of a set of specific transcriptional pathways, and apoptosis. Many of these functions are linked to protein:protein interactions involving different portions of the 1,863 amino acid (aa) BRCA1 protein. BRCA1 functions in cell cycle progression and the DNA damage response appear to be regulated by distinct and specific phosphorylation events, but the molecular pathways activated by these phosphorylations are only beginning to be unraveled. In addition, the reason that BRCA1 mutation carriers develop specific tumor types (breast and ovarian cancers in women and possibly prostate cancers in men) is not clearly understood. Elucidation of the precise molecular functions of the BRCA1 gene product will greatly enhance our understanding of the pathogenesis of hereditary as well as sporadic mammary carcinogenesis.

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“…Mammary tumor formation occurred between 10 and 13 months of age in approximately 20% of female mice with conditional inactivation of Brca1 in the luminal epithelium (Xu et al, 1999a). Mammary tumors from these mice contain several genetic abnormalities that are similar to human BRCA1-associated tumors (Weaver et al, 2002). Thus, the Wap-Cre:Brca1 and MMTV-Cre:Brca1 conditional knockout mice appear to be good models for BRCA1-associated breast cancer in humans.…”

Section: Discussionmentioning

confidence: 99%

Tumor formation in mice with conditional inactivation of Brca1 in epithelial tissues

et al. 2003

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The BRCA1 tumor-suppressor protein has been implicated in the regulation of transcription, DNA repair, proliferation, and apoptosis. BRCA1 is expressed in many proliferative tissues and this is at least in part due to E2F-dependent transcriptional control. In this study, inactivation of a conditional murine Brca1 allele was achieved in a variety of epithelial tissues via expression of the Cre recombinase under the control of a keratin 5 (K5) promoter. The K5 Cre:Brca1 conditional knockout mice exhibited modest epidermal hyperproliferation, increased apoptosis, and were predisposed to developing tumors in the skin, the inner ear canal, and the oral epithelium after 1 year of age. Overexpression of the E2F1 transcription factor in K5 Cre:Brca1 conditional knockout mice dramatically accelerated tumor development. In addition, Brca1 heterozygous female mice that had elevated E2F1 expression developed tumors of the reproductive tract at high incidence. These findings demonstrate that in mice Brca1 functions as a tumor suppressor in other epithelial tissues in addition to the mammary gland. Moreover, inactivation of Brca1 is shown to cooperate with deregulation of the Rb-E2F1 pathway to promote tumorigenesis.

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Mammary tumors in mice conditionally mutant for Brca1 exhibit gross genomic instability and centrosome amplification yet display a recurring distribution of genomic imbalances that is similar to human breast cancer

Cited by 131 publications

References 30 publications

MTA1-mediated transcriptional repression of BRCA1 tumor suppressor gene

MTA1-mediated transcriptional repression of BRCA1 tumor suppressor gene

BRCA1 gene in breast cancer

Tumor formation in mice with conditional inactivation of Brca1 in epithelial tissues

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