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

Functional inactivation of BRCA1 is an important mechanism involved in brea st cancer pathogenesis. Mutation is often responsible for BRCA1 inactivatio n in familial breast cancer, but is not responsible for the decreased level s of BRCA1 seen in a subset of sporadic breast cancer patients. To determin e if aberrant cytosine methylation of the BRCA1 promoter is associated with decreased BRCA1 gene expression in human breast cancer, high resolution bi sulfite sequence analysis was used to analyze the cytosine methylation stat us of the BRCA1 promoter in 21 axillary node negative breast cancer patient s with known levels of BRCA1 expression. Aberrant cytosine methylation of t he BRCA1 promoter was detected in three of 21 patient specimens, These thre e specimens also expressed the lowest levels of BRCA1. Results from this an alysis show that aberrant cytosine methylation of the BRCA1 promoter is dir ectly correlated with decreased levels of BRCA1 expression in human breast cancer, and suggest that epigenetic silencing may be one mechanism of trans criptional inactivation of BRCA1 in sporadic mammary carcinogenesis.