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Estrogen Receptor Mediates Breast Cancer Cell Resistance to Paclitaxel through Inhibition of Apoptotic Cell Death

¹ Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina and ² The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland

Requests for reprints: Weimin Fan, Department of Pathology and Laboratory Medicine, Medical University of South Carolina, 165 Ashley Avenue, Charleston, SC 29425. Phone: 843-792-5108; Fax: 843-792-0368; E-mail: fanw{at}musc.edu.

Estrogen receptors (ER) are expressed in 65% of human breast cancer. Cumulative data from clinical trials and retrospective analyses suggest that some chemotherapeutic agents may be less effective in patients with ER-positive (ER+) tumors than those with ER-negative (ER–) tumors. Paclitaxel is an active agent used in breast cancer chemotherapy. To investigate the possible influence of ER on the therapeutic efficacy of paclitaxel and its underlying mechanism, we established several isogenic ER+ cell lines by stable transfection of ER expression vectors into ER– breast cancer BCap37 cells. We showed that 17-ß estradiol significantly reduces the overall cytotoxicity of paclitaxel in BCap37-expressing ER but has no influence on the ER– parental cells. Further analyses indicate that expression of ER in BCap37 cells mainly interferes with paclitaxel-induced apoptotic cell death, without affecting paclitaxel-induced microtubule bundling and mitotic arrest. Moreover, we found that the addition of ICI 182,780 (Fulvestrant), a selective ER down-regulator, could completely reverse the resistance of ER+ BCap37 cells to paclitaxel. These findings showed that ER-mediated breast tumor cell resistance to paclitaxel was through selective inhibition of paclitaxel-induced tumor cell apoptosis. Additionally, the combination of ICI 182,780 also sensitizes MCF-7 and T47D cell lines to the treatment of paclitaxel, which further confirmed the correlation between ER and drug resistance in ER+ tumor cells. The results obtained from this study provide useful information for understanding ER-mediated resistance to paclitaxel and possibly other antineoplastic agents. [Cancer Res 2007;67(11):5337–44]

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