BRCA1 suppresses insulin-like growth factor-I receptor promoter activity: Potential interaction between BRCA1 and Sp1

The insulin-like growth factor I receptor (IGF-I-R) has an important role i n breast cancer etiology. The receptor is overexpressed by most breast canc ers, where it functions as a potent antiapoptotic agent. BRCA1 is a tumor s uppressor gene that is mutated in a large fraction of familial breast and o varian cancers. Cotransfection of Saos-2, MCF7, and CHO cells with IGF-I-R promoter constructs driving luciferase reporter genes, and with a BRCA1 exp ression vector, suppressed promoter activity in a dose-dependent manner. Fu nctional interactions between BRCA1 and Sp1 in the regulation of the IGF-I- R gene were studied in Schneider cells, a Drosophila cell line which lacks endogenous Spl. In these cells BRCA1 suppressed 45% of the Spl-induced tran s-activation of the IGF-I-R promoter. These results suggest that BRCA1 is c apable of suppressing the IGF-I-B promoter in a number of cell lines, thus resulting in low levels of receptor mRNA and protein. Mutant versions of BR CA1 lacking trans-activational activity can potentially derepress the IGF-I -R promoter. Activation of the over-expressed receptor by locally produced or circulating IGFs mag be a crucial step in breast and ovarian cancer prog ression. (C) 2000 Academic Press.