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 p27^Kip1^ expression. 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 p27^Kip1^ 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. 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, p27^Kip1^ and 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