| Bisphenol A at Low Nanomolar Doses Confers Chemoresistance in Estrogen Receptor-α–Positive and –Negative Breast Cancer Cells Elizabeth W. LaPensee, Traci R. Tuttle, Sejal R. Fox, and Nira Ben-Jonathan Department of Cancer and Cell Biology, University of Cincinnati, Cincinnati, Ohio, USA Abstract
Background: Resistance to chemotherapy is a major problem facing breast cancer patients, and identifying potential contributors to chemoresistance is a critical area of research. Bisphenol A (BPA) has long been suspected to promote carcinogenesis, but the high doses of BPA used in many studies generated conflicting results. In addition, the mechanism by which BPA exerts its biological actions is unclear. Although estrogen has been shown to antagonize anticancer drugs, the role of BPA in chemoresistance has not been examined. Objective: The objective of our study was to determine whether BPA at low nanomolar concentrations opposes the action of doxorubicin, cisplatin, and vinblastine in the estrogen receptor-α (ERα) -positive T47D and the ERα-negative MDA-MB-468 breast cancer cells. Methods: We determined the responsiveness of cells to anticancer drugs and BPA using the 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyl tetrazolium bromide (MTT) cytotoxicity assay. Specific ERα and ERβ inhibitors and real-time polymerase chain reaction were used to identify potential receptor(s) that mediate the actions of BPA. Expression of antiapoptotic proteins was assessed by Western blotting. Results: BPA antagonizes the cytotoxicity of multiple chemotherapeutic agents in both ERα-positive and -negative breast cancer cells independent of the classical ERs. Both cell types express alternative ERs, including G-protein–coupled receptor 30 (GPR30) and members of the estrogen-related receptor family. Increased expression of antiapoptotic proteins is a potential mechanism by which BPA exerts its anticytotoxic effects. Conclusions: BPA at environmentally relevant doses reduces the efficacy of chemotherapeutic agents. These data provide considerable support to the accumulating evidence that BPA is hazardous to human health. Key words: bisphenol A, breast cancer cells, chemotherapeutic agents, cytotoxicity, estrogen receptors. Environ Health Perspect 117:175–180 (2009) . doi:10.1289/ehp.11788 available via http://dx.doi.org/ [Online 8 October 2008]
Address correspondence to N. Ben-Jonathan, Department of Cancer and Cell Biology, University of Cincinnati, 3125 Eden Ave., Cincinnati, OH 45267-0521 USA. Telephone: (513) 558-4821. Fax: (513) 558-4823. E-mail: Nira.Ben-Jonathan@uc.edu This work was supported by National Institutes of Health (NIH) grants ES012212 and CA096613, Department of Defense grant BC05725 and Susan G. Komen Breast Cancer Foundation grant BCRT87406 to N.B.-J., and NIH training grant 5T32ES007250 to E.W.L. The authors declare they have no competing financial interests. Received 11 June 2008 ; accepted 6 October 2008.
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