Functional and Physical Interactions between BRCA1 and p53 in Transcriptional Regulation of the IGF-IR Gene

Abstract

The insulin-like growth factor-I receptor (IGF-IR) mediates the biological actions of the IGFs, and is critical for normal mammary gland development as well as for malignant transformation. Transcription of the IGF-IR gene is under inhibitory control by a number of transcription factors with tumor suppressor activity, including BRCA1 and p53. To assess the potential functional interactions between BRCA1 and p53 in transcriptional control of the IGF-IR gene, co-transfections were performed on MCF-7 breast cancer cells using an IGF-IR promoter luciferase reporter construct together with expression vectors encoding BRCA1 and wild-type and mutant p53. Similar experiments were performed in the colorectal cancer cell line HCT116^+/+, which expresses a wild-type p53 gene, and its HCT116^-/- derivative, which lacks p53. BRCA1 was able to suppress IGF-IR promoter activity both in the absence and presence of p53. However, BRCA1 had no effect in mutant p53-expressing cells. Co-immunoprecipitation experiments showed that BRCA1 and p53 physically interact. In summary, our data suggest that the transcriptional activity of BRCA1 depends on the cellular status of p53. Inability of mutant tumor suppressors to repress IGF-IR gene expression may result in increased IGF-IR levels and IGF binding, leading to a reduction in apoptosis and enhanced survival capacity of malignant cells.