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.