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Research Articles: Therapeutics, Targets, and Development

A new mechanism of drug resistance in breast cancer cells: fatty acid synthase overexpression-mediated palmitate overproduction

Department of Pharmacology and Toxicology, Walther Oncology Center/Walther Cancer Institute and Indiana University Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana

Requests for reprints: Jian-Ting Zhang, Indiana University Cancer Center, Indiana University School of Medicine, 1044 West Walnut Street, R4-166, Indianapolis, IN 46202. Phone: 317-278-4503; Fax: 317-274-8046. E-mail: jianzhan{at}iupui.edu

Abstract

Multidrug resistance is a major problem in successful cancer chemotherapy. Various mechanisms of resistance, such as ABC transporter-mediated drug efflux, have been discovered using established model cancer cell lines. While characterizing a drug-resistant breast cancer cell line, MCF7/AdVp3000, we found that fatty acid synthase (FASN) is overexpressed. In this study, we showed that ectopic overexpression of FASN indeed causes drug resistance and that reducing the FASN expression increased the drug sensitivity in breast cancer cell lines MCF7 and MDA-MB-468 but not in the normal mammary epithelial cell line MCF10A1. Use of FASN inhibitor, Orlistat, at low concentrations also sensitized cells with FASN overexpression to anticancer drugs. The FASN-mediated drug resistance appears to be due to a decrease in drug-induced apoptosis from an overproduction of palmitic acid by FASN. Together with previous findings of FASN as a poor prognosis marker for breast cancer patients, our results suggest that FASN overexpression is a new mechanism of drug resistance and may be an ideal target for chemosensitization in breast cancer chemotherapy. [Mol Cancer Ther 2008;7(2):263–70]

Grant support: Department of Defense grant DAMD17-03-1-0566, NIH grants CA94961 and CA120221, and Department of Defense Breast Cancer Research Program predoctoral traineeship W81XWH-06-1-0490 (H. Liu).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 6/29/07; revised 11/ 5/07; accepted 12/20/07.