Tumour-specific distribution of BRCA1 promoter region methylation supports a pathogenetic role in breast and ovarian cancer

Abstract

The role of BRCA1 in sporadic breast and ovarian cancers remains elusive. Direct involvement of BRCA1 in the development of breast and ovarian cancer is suggested by the finding that the BRCA1 promoter region CpG island is methylated in a proportion of breast and ovarian cancers. The aim of this study was to compare the incidence of BRCA1 promoter region methylation in tumours in which loss of BRCA1 has been shown to play a role in pathogenesis (breast and ovarian carcinomas) with the incidence in tumours in which BRCA1 is unlikely to play a role in pathogenesis. Promoter region hypermethylation was significantly more common (P < 0.008) in breast and ovarian cancer (6/38 tumours methylated) than in colon cancer (0/35 tumours methylated) or in leukaemias (0/19 samples methylated). The restriction of BRCA1 promoter region hypermethylation to breast and ovarian cancer is consistent with a pathogenetic role of BRCA1 promoter methylation in these tumours. We suggest that the rarity of observed BRCA1 mutations in sporadic breast and ovarian cancer is due to the greater likelihood of BRCA1 inactivation by non-mutational mechanisms such as methylation.

Reduced BRCA1 expression due to promoter hypermethylation in therapy-related acute myeloid leukaemia

“…BRCA1 hypermethylation has not been previously reported in AML. Using a Southern blot technique, Bianco et al (2000) did not find methylation of BRCA1 in 19 leukaemia samples, including 11 samples from patients with AML. Using MS-PCR, Esteller et al (2001) reported no BRCA1 methylation in 19 leukaemia samples, but did not specify the type of leukaemias studied.…”

“…The frequency of BRCA1 methylation in our AML patients is similar to that of patients with breast, ovarian and pancreatic carcinomas. Other tumour types as colon cancer and hepatocellular carcinomas did not show aberrant BRCA1 methylation (Bianco et al, 2000;Esteller et al, 2001). When analysing primary tumour samples of patients with secondary AML, we found BRCA1 hypermethylation only in breast cancer samples.…”

CD40-induced transcriptional activation of vascular endothelial growth factor involves a 68-bp region of the promoter containing a CpG island

“…Recent evidence suggests that CpG dinucleotides within a promoter play a significant role in gene silencing via an ability to bind transcriptional repressor proteins (3,29). We demonstrate that the CpG island within the CD40-responsive region of the VEGF promoter binds the transcriptional repressor protein methyl CpG binding protein-2 (MeCP2) and perhaps other CpG binding proteins, and we show that MeCP2 is removed following CD40-dependent activation of EC.…”

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

“…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.…”