Down-regulation of BRCA1 in human sporadic breast cancer; analysis of DNA methylation patterns of the putative promoter region

Germ-line alterations of BRCA1 are responsible for about 50% of familial br east cancers. Although its biological function(s) has not yet been fully de termined, it has been suggested that it may act as a tumor suppressor gene in breast and ovarian cancers. In sporadic breast cancers alterations of BR CA1 have not been detected and in vitro experiments have indicated that BRC A1 negatively regulates cellular proliferation, The present study was desig ned to identify and quantify, the BRCA1 mRNA levels, in normal and neoplasi c human breast tissue, BRCA1 mRNA molecules were quantified using competiti ve reverse transcriptase PCR assays. DNA methylation patterns of this gene have been analysed by Southern blot experiments using methylation sensitive restriction enzymes. We found that BRCA1 mRNA levels were significantly lo wer in sporadic breast cancers (37 cases analysed, 24 cases of invasive duc tal carcinomas not otherwise specified (NOS), two lobular carcinomas in sit u two medullary carcinomas, four invasive lobular carcinomas, two invasive mucinous carcinomas and three invasive ductal carcinomas with predominantly in situ component) compared with normal breast tissues (P = 0.0003), This down-regulation of BRCA1 is observed in all histologic types analysed. In i nvasive ductal carcinomas NOS, this down-regulation does not correlate with any of the prognostic factors studied (tumor size, node status, histologic grade, hormone receptor status), In the samples analysed, alterations of D NA methylation patterns were not dectected in the vicinity of the major tra nscription start site, These data suggest the involvement of BRCA1 in the c arcinogenesis of these histologic types.