Antimicrotubule agents are commonly used
chemotherapy drugs for the treatment of breast and other
cancers. However, these agents have variable activity partly because of microtubule regulatory
proteins.
Stathmin, an 18-kDa
phosphoprotein that promotes microtubule depolymerization, was found to be frequently overexpressed in
breast cancer. We previously identified
stathmin-mediated mechanisms of resistance to antimicrotubule agents, including altered
drug binding and delayed transit from G(2) into M phase, where these agents are effective in disrupting microtubule dynamics. We hypothesized that by reversing
stathmin-mediated depolymerization of microtubules or by promoting entry into mitosis, this could increase sensitivity to antimicrotubule agents in human
breast cancer cells overexpressing
stathmin. We found that targeting
stathmin or wee-1 expression with RNA interference can induce microtubule polymerization and promote G(2)/M progression, respectively, and sensitize
stathmin-overexpressing
breast cancer cells to
paclitaxel and
vinblastine. Furthermore, targeting wee-1 led to the phosphorylation of
stathmin, which is known to attenuate its activity. Therefore, these data suggest a novel approach to improving the efficacy of certain antimicrotubule agents against
breast cancer by regulating the function of
stathmin.