Prognostic significance of BRCA1 expression in Japanese sporadic breast carcinomas

Yang, Qifeng; Sakurai, Takeo; Mori, Ichiro; Yoshimura, Goro; Nakamura, Misa; Nakamura, Yasushi; Suzuma, Takaomi; Tamaki, Takeshi; Umemura, Teiji; Kakudo, Kennichi

doi:10.1002/1097-0142(20010701)92:1<54::aid-cncr1291>3.0.co;2-8

Cited by 88 publications

(76 citation statements)

References 31 publications

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“…Although inherited mutations of BRCA1 account for a small minority of all breast cancers (2.5-5%), BRCA1 may play a much wider role, in many sporadic cancers. Thus, 30-40% of sporadic breast cancers show reduced expression of BRCA1 mRNA and protein relative to the uninvolved normal breast, particularly tumors with high nuclear grade (Thompson et al, 1995;Taylor et al, 1998;Lee et al, 1999;Wilson et al, 1999;Yang et al, 2001). The mechanisms of the observed down-regulation of BRCA1 in sporadic human breast cancers is unclear, but may involve some of the transcriptional pathways described above.…”

Section: Regulation Of Brca1 Expressionmentioning

confidence: 99%

BRCA1 gene in breast cancer

Rosen

Fan

Pestell

et al. 2003

Journal Cellular Physiology

233

189

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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: Regulation Of Brca1 Expressionmentioning

confidence: 99%

BRCA1 gene in breast cancer

Rosen

Fan

Pestell

et al. 2003

Journal Cellular Physiology

233

189

View full text Add to dashboard Cite

show abstract

“…They show a high incidence of accompanying p53 mutations, impaired differentiation and poor clinical outcome compared with other breast cancer subtypes. Downregulation of BRCA1 mRNA and protein expression has also been reported in approximately 30% of sporadic breast cancers (Yang et al, 2001). Sporadic basal-like breast cancers (BLBCs) share many features with BRCA1 mutant breast cancers indicating a potential common defect, previously described as 'BRCAness' (Turner et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

BRCA1 and GATA3 corepress FOXC1 to inhibit the pathogenesis of basal-like breast cancers

et al. 2011

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In this study we describe a novel interaction between the breast/ovarian tumor suppressor gene BRCA1 and the transcription factor GATA3, an interaction, which is important for normal breast differentiation. We show that the BRCA1-GATA3 interaction is important for the repression of genes associated with triple-negative and basal-like breast cancer (BLBCs) including FOXC1, and that GATA3 interacts with a C-terminal region of BRCA1. We demonstrate that FOXC1 is an essential survival factor maintaining the proliferation of BLBCs cell lines. We define the mechanistic basis of this corepression and identify the GATA3-binding site within the FOXC1 distal promoter region. We show that BRCA1 and GATA3 interact on the FOXC1 promoter and that BRCA1 requires GATA3 for recruitment to this region. This interaction requires fully functional BRCA1 as a mutant BRCA1 protein is unable to localize to the FOXC1 promoter or repress FOXC1 expression. We demonstrate that this BRCA1-GATA3 repression complex is not a FOXC1-specific phenomenon as a number of other genes associated with BLBCs such as FOXC2, CXCL1 and p-cadherin were also repressed in a similar manner. Finally, we demonstrate the importance of our findings by showing that loss of GATA3 expression or aberrant FOXC1 expression contributes to the drug resistance and epithelial-to-mesenchymal transition-like phenotypes associated with aggressive BLBCs.

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“…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. 6 However, the specific functions of the BRCA1 protein that contribute to tumor suppression remain to be defined.…”

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

150

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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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Prognostic significance of BRCA1 expression in Japanese sporadic breast carcinomas

Cited by 88 publications

References 31 publications

BRCA1 gene in breast cancer

BRCA1 gene in breast cancer

BRCA1 and GATA3 corepress FOXC1 to inhibit the pathogenesis of basal-like breast cancers

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

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