Bisphenol A at low nanomolar doses confers chemoresistance in estrogen receptor-alpha-positive and -negative breast cancer cells.
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-alpha (ERalpha)-positive T47D and the ERalpha-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 ERalpha and ERbeta 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 ERalpha-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.
Lapensee
Elizabeth W
EW
Department of Cancer and Cell Biology, University of Cincinnati, Cincinnati, Ohio 45267-0521, USA. Nira.Ben-Jonathan@uc.edu
Tuttle
Traci R
TR
Fox
Sejal R
SR
Ben-Jonathan
Nira
N
D017209:Apoptosis / Q000187:drug effects; D001559:Benzhydryl Compounds; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D004347:Drug Interactions; D004351:Drug Resistance / Q000187:drug effects*; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors*; D000077267:Fulvestrant; D006801:Humans; D010636:Phenols / Q000494:pharmacology*; D014747:Vinblastine / Q000494:pharmacology; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D002945:Cisplatin; D004317:Doxorubicin; D004958:Estradiol; D047628:Estrogen Receptor alpha; D000077267:Fulvestrant; D010636:Phenols; D014747:Vinblastine; C006780:bisphenol A; D000098826:Bisphenol A Compounds