Decreased expression of BRCA1 may play a role in the etiology of sporadic breast cancer. Deletion and point mutant analysis of proximal promoter elements in the BRCA1 1a promoter revealed a 22 bp region which was critical for the expression of the promoter in MCF-7 cells, but had a much reduced e ect in T47D cells. The main transcription factor interacting with this site was identi®ed as GABPa/b, and a discrete DNA binding complex was only observed in nuclear extracts from MCF-7 cells. Cotransfection experiments with GABPa and b1 expression vectors produced transactivation of this element in both lines. These results suggest that GABPa/b is a critical activator of BRCA1 expression, and that its activity may di er in human breast cell lines.

Transcriptional regulation of the BRCA1 proximal promoter has been suggested to play a role in the decreased expression of BRCA1 observed in sporadic breast cancer. Computer analysis of the sequence of the proximal promoter reveals the presence of a potential CREB site. We have identi®ed CREB/ATF-1 as the factor interacting with this site in nuclear extracts from MCF-7 and T-47D cells. This site is shown to be important for the constitutive expression of the promoter in these cells, as well as in Hep G2 cells. Despite the presence of this site, the BRCA1 promoter is not responsive to cAMP induction. It appears that CREB acts as a constitutive positive element for BRCA1 expression and that any mechanism inactivating CREB function would have a dramatic e ect on BRCA1 expression. Oncogene (2001) 20, 7110 ± 7114.