Methylation of the BRCA1 promoter is associated with decreased BRCA1 mRNA levels in clinical breast cancer specimens

Rice, Judd C.; Özçelik, Hilmi; Maxeiner, Patrick; Andrulis, Irene L.; Futscher, Bernard W.

doi:10.1093/carcin/21.9.1761

Cited by 202 publications

(143 citation statements)

References 24 publications

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“…Although somatic BRCA1 mutation is rare in sporadic tumors, reduced expression of BRCA1 protein has been detected in 10-25% of sporadic breast and ovarian cancers. 5,[54][55][56] Therefore, the status of BRCA1 might be a determinant of the efficacy of paclitaxel response in breast and ovarian cancers. Twenty-four hours after transfection with pcDNA3-BRCA1 or control pcDNA3, cells were harvested, lysed and subjected to protein immunoblot analysis using anti-BubR1, anti-BRCA1 and anti-HSP60 antibodies.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Evidence of a role for BRCA1 in sporadic mammary carcinogenesis supports this idea. Thus, BRCA1 expression is decreased or absent in a significant proportion of sporadic breast and ovarian cancer cases, in part because of hypermethylation of the BRCA1 promoter on CpG islands (Wilson et al, 1999;Rice et al, 2000). A significant fraction of sporadic breast cancers (46%) were found to be haploinsufficient for BRCA1 (Staff et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

BRCA1 and BRCA2 as molecular targets for phytochemicals indole-3-carbinol and genistein in breast and prostate cancer cells

et al. 2006

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Indole-3-carbinol (I3C) and genistein are naturally occurring chemicals derived from cruciferous vegetables and soy, respectively, with potential cancer prevention activity for hormone-responsive tumours (e.g., breast and prostate cancers). Previously, we showed that I3C induces BRCA1 expression and that both I3C and BRCA1 inhibit oestrogen (E2)-stimulated oestrogen receptor (ER-a) activity in human breast cancer cells. We now report that both I3C and genistein induce the expression of both breast cancer susceptibility genes (BRCA1 and BRCA2) in breast (MCF-7 and T47D) and prostate (DU-145 and LNCaP) cancer cell types, in a time-and dosedependent fashion. Induction of the BRCA genes occurred at low doses of I3C (20 mM) and genistein (0.5 -1.0 mM), suggesting potential relevance to cancer prevention. A combination of I3C and genistein gave greater than expected induction of BRCA expression. Studies using small interfering RNAs (siRNAs) and BRCA expression vectors suggest that the phytochemical induction of BRCA2 is due, in part, to BRCA1. Functional studies suggest that I3C-mediated cytoxicity is, in part, dependent upon BRCA1 and BRCA2. Inhibition of E2-stimulated ER-a activity by I3C and genistein was dependent upon BRCA1; and inhibition of ligand-inducible androgen receptor (AR) activity by I3C and genistein was partially reversed by BRCA1-siRNA. Finally, we provide evidence suggesting that the phytochemical induction of BRCA1 expression is due, in part, to endoplasmic reticulum stress response signalling. These findings suggest that the BRCA genes are molecular targets for some of the activities of I3C and genistein.

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“…In addition to these studies, we used high resolution bisulfite sequencing to identify aberrant cytosine methylation of the BRCA1 5′ CpG island in three of 21 sporadic breast cancer specimens. These three specimens also expressed the lowest levels of BRCA1 transcript by RT-PCR analysis (18). We hypothesized that the aberrant cytosine methylation of the BRCA1 promoter is associated with histone hypoacetylation, chromatin condensation and transcriptional repression of BRCA1 in sporadic breast cancer.…”

Section: Introductionmentioning

confidence: 96%

“…In contrast, the region upstream of -728, although still CpG rich, was methylated in both normal cells and breast cancer cell lines. The non-methylated domain contains maximal BRCA1 promoter activity and is the target region for aberrant cytosine methylation in breast cancer cells (17)(18)(19)(20). We identified one BRCA1-negative sporadic breast cancer cell line that was aberrantly methylated at all 75 CpG dinucleotides analyzed.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional repression of BRCA1 by aberrant cytosine methylation, histone hypoacetylation and chromatin condensation of the BRCA1 promoter

Rice¹

2000

Nucleic Acids Research

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BRCA1 expression is repressed by aberrant cytosine methylation in sporadic breast cancer. We hypothesized that aberrant cytosine methylation of the BRCA1 promoter was associated with the transcriptionally repressive effects of histone hypoacetylation and chromatin condensation. To address this question, we developed an in vitro model of study using normal cells and sporadic breast cancer cells with known levels of BRCA1 transcript to produce a 1.4 kb 5-methylcytosine map of the BRCA1 5′ CpG island. While all cell types were densely methylated upstream of -728 relative to BRCA1 transcription start, all normal and BRCA1 expressing cells were non-methylated downstream of -728 suggesting that this region contains the functional BRCA1 5′ regulatory region. In contrast, the non-BRCA1 expressing UACC3199 cells were completely methylated at all 75 CpGs. Chromatin immunoprecipitations showed that the UACC3199 cells were hypoacetylated at both histones H3 and H4 in the BRCA1 promoter compared to non-methylated BRCA1 expressing cells. The chromatin of the methylated UACC3199 BRCA1 promoter was inaccessible to DNA-protein interactions. These data indicate that the epigenetic effects of aberrant cytosine methylation, histone hypoacetylation and chromatin condensation act together in a discrete region of the BRCA1 5′ CpG island to repress BRCA1 transcription in sporadic breast cancer.

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Methylation of the BRCA1 promoter is associated with decreased BRCA1 mRNA levels in clinical breast cancer specimens

Cited by 202 publications

References 24 publications

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

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

BRCA1 and BRCA2 as molecular targets for phytochemicals indole-3-carbinol and genistein in breast and prostate cancer cells

Transcriptional repression of BRCA1 by aberrant cytosine methylation, histone hypoacetylation and chromatin condensation of the BRCA1 promoter

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