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Reversal of Stathmin-Mediated Resistance to Paclitaxel and Vinblastine in Human Breast Carcinoma Cells

The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, Departments of Medicine (J.-M.Y, W.N.H.) and Pharmacology (E.A., J.-M.Y, W.N.H.), New Brunswick, New Jersey; and Division of Oncology, Stanford University School of Medicine, Stanford, California (J.F.)

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 G₂ 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 G₂/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.

Address correspondence to: William N. Hait, The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey/Robert Wood Johnson Medical School, 195 Little Albany Street, New Brunswick, NJ 08901. E-mail: haitwn{at}umdnj.edu

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