Interaction of BRCA1 and p27Kip1 Pathway in Breast Cancer
Annual summary rept. 1 May 2002-30 Apr 2005
CEDARS-SINAI MEDICAL CENTER LOS ANGELES CA
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Women who have familial breast cancer often have a germline mutation of the breast cancer susceptibility gene known as BRCA1. The function of BRCA1 is not totally understood. Previously we observed a correlation between the expression of BRCA1 and p27kip1 in a serie of breast cancer cell lines. The p27kip1 is a member of the universal cyclin-dependent kinase inhibitor family. We have shown that BRCA1 can transcriptionally activate the p27kip promoter. The BRAC1-responsive element was defined as a 35 bp region from position -545 to -511. We determined that within this region is also a potential binding site for the transcription factor FOXA1. FOXA1 could activate the p27Kipl promoter. Co-transfection of BRCA1 and FOXA1 resulted in a synergistic activation of the p27KiPl promoter. Mutation of the FOXA1 DNA binding site in the p27Kipl promoter significantly diminished the activity of FOXA1 alone or in combination with BRCA1. EMSA analysis demonstrated that FOXA1 could bind to the p27kip1 promoter. Using siRNA to suppress BRCA1 protein levels, we observed decreasec p27kip1 promoter activity and reduced FOXA1 protein expression. Co-immunoprecipitation experiments indicated that FOXA1 and BRCA1 proteins interacted in vivo. In summary we discovered a role for BRCA1 in the regulation of p27Kip1 transcription and a possible interaction with FOXA1, and we identified high expression of FOXA1 in breast cancer cell lines and tissues.
- Medicine and Medical Research