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Background  The  BRCA1  gene plays an important role in the maintenance of genomic stability. BRCA1 inactivation contributes to breast cancer tumorigenesis. An increasing number of transcription factors have been shown to regulate  BRCA1  expression. c-Myc can act as a transcriptional activator, regulating up to 15% of all genes in the human genome and results from a high throughput screen suggest that  BRCA1  is one of its targets. In this report, we used cultured breast cancer cells to examine the mechanisms of transcriptional activation of  BRCA1  by c-Myc.    Methods  c-Myc was depleted using c-Myc-specific siRNAs in cultured breast cancer cells.  BRCA1  mRNA expression and BRCA1 protein expression were determined by quantitative RT-PCR and western blot, respectively and  BRCA1  promoter activities were examined under these conditions. DNA sequence analysis was conducted to search for high similarity to E boxes in the  BRCA1  promoter region. The association of c-Myc with the  BRCA1  promoter  in vivo  was tested by a chromatin immunoprecipitation assay. We investigated the function of the c-Myc binding site in the  BRCA1  promoter region by a promoter assay with nucleotide substitutions in the putative E boxes. BRCA1-dependent DNA repair activities were measured by a GFP-reporter assay.    Results  Depletion of c-Myc was found to be correlated with reduced expression levels of  BRCA1  mRNA and BRCA1 protein. Depletion of c-Myc decreased  BRCA1  promoter activity, while ectopically expressed c-Myc increased  BRCA1  promoter activity. In the distal  BRCA1  promoter, DNA sequence analysis revealed two tandem clusters with high similarity, and each cluster contained a possible c-Myc binding site. c-Myc bound to these regions  in vivo . Nucleotide substitutions in the c-Myc binding sites in these regions abrogated c-Myc-dependent promoter activation. Furthermore, breast cancer cells with reduced BRCA1 expression due to depletion of c-Myc exhibited impaired DNA repair activity.    Conclusions  The distal  BRCA1  promoter region is associated with c-Myc and contributes to  BRCA1  gene activation.

c-Myc activates BRCA1 gene expression through distal promoter elements in breast cancer cells