Germ-Line<i>BRCA1</i>Mutations in Jewish and Non-Jewish Women with Early-Onset Breast Cancer

FitzGerald, Michael G.; MacDonald, Deborah J.; Krainer, Michael; Hoover, Ingrid; O’Neil, Erin; Ünsal, Hilal; Silva-Arrieto, Sandra; Finkelstein, Dianne M.; Beer-Romero, Peggy; Englert, Christoph; Sgroi, Dennis; Smith, Barbara L.; Younger, Jerry; Garber, Judy E.; Duda, Rosemary B.; Mayzel, Kathleen; Isselbacher, Kurt J.; Friend, Stephen H.; Haber, Daniel A.

doi:10.1056/nejm199601183340302

Cited by 365 publications

(179 citation statements)

References 19 publications

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“…The risk of developing breast cancers at a very early age-before 40 or even 30 years-is substantially elevated in BRCA1 mutation carriers. Thus, among women who developed breast cancer before age 30, about 10-15% were found to carry mutations of either BRCA1 or BRCA2 (Fitzgerald et al, 1996;Peto et al, 1999). Nevertheless, for BRCA1 mutation carriers, the risk of developing breast cancer continues throughout life.…”

Section: Clinical Perspectives Hereditary Brca1 Mutant Breast Cancersmentioning

confidence: 99%

BRCA1 gene in breast cancer

Rosen

Fan

Pestell

et al. 2003

Journal Cellular Physiology

241

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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Section: Clinical Perspectives Hereditary Brca1 Mutant Breast Cancersmentioning

confidence: 99%

BRCA1 gene in breast cancer

Rosen

Fan

Pestell

et al. 2003

Journal Cellular Physiology

241

195

View full text Add to dashboard Cite

show abstract

“…1,2 In addition, absent or reduced BRCA1 expression due to promoter methylation is commonly observed in sporadic breast and ovarian cancer, implicating BRCA1 in non hereditary tumors. [3][4][5] Established functional roles of BRCA1 include regulation of cell cycle progression, DNA damage signaling and repair, maintenance of genome integrity, ubiquitination and regulation of transcription.…”

Section: Introductionmentioning

confidence: 99%

BRCA1 Downregulation Leads to Premature Inactivation of Spindle Checkpoint and Confers Paclitaxel Resistance

Chabalier¹,

Lamare²,

Racca³

et al. 2006

Cell Cycle

151

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BRCA1 germline mutations predispose women to early onset, familial breast and ovarian cancer. BRCA1 has been recently implicated in the cellular response to agents that disrupt the mitotic spindle. In this report, we studied BRCA1 contribution to paclitaxel response in MCF-7 breast cancer cells. We show that MCF-7 cells transfected with BRCA1 siRNA display a significant increase in resistance to paclitaxel compared with the control cells. We next demonstrate that downregulation of BRCA1 reduces the mitotic index and triggers premature cyclin B1 degradation and decrease in Cdk1 activity following paclitaxel treatment, suggesting that BRCA1 downregulation results in precocious inactivation of the spindle checkpoint. These findings were confirmed by showing that BRCA1 downregulation induces premature sister-chromatids separation in MCF-7 cells following spindle damage. Furthermore, we show that BRCA1 up-regulates the expression of the protein kinase BubR1, essential component of the functional spindle checkpoint, whose downregulation is known to result in paclitaxel resistance in MCF-7 cells. Altogether, our findings support the notion that downregulation of BRCA1 expression mediates paclitaxel resistance through premature inactivation of spindle checkpoint in MCF-7 breast cancer cells. They link BRCA1 to the mitotic checkpoint that plays an essential role in the maintenance of chromosomal stability.

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“…Germ line mutations of BRCA1 are found in f80% of breastovarian cancer pedigrees and in f10% of women with earlyonset breast cancer irrespective of family history (3). Other reports have implied that BRCA1 may also play an important role in the sporadic form of the disease because up to 30% of sporadic breast cancers exhibit reduced BRCA1 protein expression levels (4).…”

Section: Introductionmentioning

confidence: 99%

BRCA1 Regulates IFN-γ Signaling through a Mechanism Involving the Type I IFNs

Buckley

Hosey

Gorski

et al. 2007

Molecular Cancer Research

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BRCA1 encodes a tumor suppressor gene that is mutated in the germ line of women with a genetic predisposition to breast and ovarian cancer. BRCA1 has been implicated in a number of important cellular functions including DNA damage repair, transcriptional regulation, cell cycle control, and ubiquitination. Using an Affymetrix U95A microarray, IRF-7 was identified as a BRCA1 transcriptional target and was also shown to be synergistically up-regulated by BRCA1 specifically in the presence of IFN-;, coincident with the synergistic induction of apoptosis. We show that BRCA1, signal transducer and activator of transcription (STAT)-1, and STAT2 are all required for the induction of IRF-7 following stimulation with IFN-;. We also show that the induction of IRF-7 by BRCA1 and IFN-; is dependent on the type I IFNs, IFN-A and IFN-B. We show that BRCA1 is required for the up-regulation of STAT1, STAT2, and the type I IFNs in response to IFN-;. We show that BRCA1 is localized at the promoters of the molecules involved in type I IFN signaling leading to their up-regulation. Blocking this intermediary type I IFN step using specific antisera shows the requirement for IFN-A and IFN-B in the induction of IRF-7 and apoptosis. Finally, we outline a mechanism for the BRCA1/IFN-; regulation of target genes involved in the innate immune response, which is dependent on type I IFN signaling. (Mol Cancer Res 2007;5(3):261 -70)

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Germ-LineBRCA1Mutations in Jewish and Non-Jewish Women with Early-Onset Breast Cancer

Abstract: Germ-line BRCA1 mutations can be present in young women with breast cancer who do not belong to families with multiple affected members. The specific BRCA1 mutation known as 185delAG is strongly associated with the onset of breast cancer in Jewish women before the age of 40.

Cited by 365 publications

References 19 publications

BRCA1 gene in breast cancer

BRCA1 gene in breast cancer

BRCA1 Downregulation Leads to Premature Inactivation of Spindle Checkpoint and Confers Paclitaxel Resistance

BRCA1 Regulates IFN-γ Signaling through a Mechanism Involving the Type I IFNs

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