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

Abstract

BRCA1 is a multifunctional tumor-suppressive protein. Many functional aspects of BRCA1 are not fully understood. We used a shRNA approach to probe the function of BRCA1 in human breast cancer cells. Knocking down BRCA1 expression by shRNA 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 p27Kip1expression. In BRCA1 knocked-down cells, the expression of survivin 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 p27Kip1by 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. Increase resistance to paclitaxel was due to an increase in the expression of survivin in both the BRCA1 knocked-down and mutant BRCA1 cells because knocking down survivin expression by siRNA restored sensitivity to paclitaxel. We conclude that BRCA1 down-modulates the malignant behavior of breast cancer cells, promotes the expression of p21/Waf1, p27Kip1and inhibits the expression of survivin. Moreover, loss of BRCA1 expression or function leads to an increase in survivin expression and a reduction in chemosensitivity to paclitaxel. © 2009 UICC.