Interaction of BRCA1 and p27(kip1) Pathway in Breast Cancer

摘要

Women who have familial breast cancer often have a germline mutation of the breast cancer susceptibility gene known as BRCAl. The function of BRCAl is not totally understood. BRCAl has a number of activities including DNA repair, growth inhibition, and as a transcription factor. The p27(exp kiP1) is a member of the universal cyclin-dependent kinase inhibitor family. In this study we have shown that BRCAl can transcriptionally activate the p27(exp KiP1) promoter. This transactivation is dependent on the presence of a functional C- terminal domain. The BRCAl-responsive element was defined from position -545 to -511. We next determined that within this region is also a potential binding site for the transcription factor FOXAl. In transient transfection reporter assays, FOXAl could activate the p27(exp KiP1) promoter. Co transfection of BRCAl and FOXAl resulted in a synergistic activation of the p27(exp KiP1) promoter. Mutation of the FOXAl DNA binding site in the p27(exp KiP1) promoter- luciferase construct significantly diminished the activity of FOXAl alone or in combination with BRCAl. EMSA analysis demonstrated that FOXAl could bind to the p27kip1 promoter, but this binding was lost upon mutation of the FOXAl binding site. Co-immunoprecipitation experiments indicated that FOXAl and BRCAl proteins interacted in vivo.