BRCA1-Sp1 interactions in transcriptional regulation of the IGF-IR gene.

The insulin-like growth factor-I receptor (IGF-IR) plays a critical role in breast tumorigenesis and is overexpressed in most primary tumors. BRCA1 is a transcription factor involved in numerous cellular processes, including DNA damage repair, cell growth, and apoptosis. Consistent with its tumor suppressor role, we demonstrated that BRCA1 repressed the activity of co-transfected IGF-IR promoter reporter constructs in a number of breast cancer-derived cell lines. Results of electrophoretic mobility shift assay showed that BRCA1 did not exhibit any specific binding to the IGF-IR promoter, although it prevented binding of Sp1. Co-immunoprecipitation experiments demonstrated that BRCA1 action was associated with specific interaction with Sp1 protein. Furthermore, using a series of glutathione S-transferase-tagged BRCA1 fragments, we mapped the Sp1-binding domain to a segment located between aa 260 and 802. In summary, our data suggest that the IGF-IR gene is a novel downstream target for BRCA1 action.