Abstract #4440: BRCA1 modulates malignant cell behavior, the expression of survivin and chemosensitivity in human breast cancer cells

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO BRCA1 is a multi-functional tumor-suppressive protein and much of its function is not fully understood. In this study we used a shRNA approach to probe the function of BRCA1. Knocking down BRCA1 expression by shRNAs in the wild type BRCA1 human breast cancer MCF-7 and MDA-MB-231 cells resulted in an increase in cell proliferation, anchorage-independent growth, cell migration, invasion and a loss of p21/Waf1 and p27Kip1 expression. The expression of the anti-apoptotic protein survivin, on the other hand, was significantly up-regulated with a concurrent decrease in cellular sensitivity to paclitaxel. We also found that cells harboring endogenous mutant or defective BRCA1 (MDA-MB-436 and HCC1937) were highly proliferative and expressed a relatively low level of p21/Waf1 and p27Kip1 by comparison to wild type BRCA1 cells. Cells harboring mutated BRCA1 also expressed a high level of survivin and were relatively resistant to paclitaxel by comparison to wild type cells. It is concluded that the tumor-suppressive function of BRCA1 is intimately linked to the attenuation of malignant cell behavior. BRCA1 functions to promote the expression of p21/Waf1 and p27Kip1 but inhibit the expression of survivin. Loss of BRCA1 expression leads to an increase in survivin expression and a reduction in chemosensitivity to paclitaxel. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4440.