Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

J. Biol. Chem. 284 (13): 8633-8642

© 2009 by The American Society for Biochemistry and Molecular Biology, Inc.

Estrogen Receptor {alpha} Enhances the Rate of Oxidative DNA Damage by Targeting an Equine Estrogen Catechol Metabolite to the Nucleus*

Zhican Wang, Gihani T. Wijewickrama, Kuan-wei Peng, Birgit M. Dietz, Long Yuan, Richard B. van Breemen, Judy L. Bolton1, , and Gregory R. J. Thatcher2

Department of Medicinal Chemistry and Pharmacognosy (M/C 781), College of Pharmacy, University of Illinois, Chicago, Illinois 60612-7231

Abstract: Exposure to estrogens increases the risk of breast and endometrial cancer. It is proposed that the estrogen receptor (ER) may contribute to estrogen carcinogenesis by transduction of the hormonal signal and as a "Trojan horse" concentrating genotoxic estrogen metabolites in the nucleus to complex with DNA, enhancing DNA damage. 4-Hydroxyequilenin (4-OHEN), the major catechol metabolite of equine estrogens present in estrogen replacement formulations, autoxidizes to a redox-cycling quinone that has been shown to cause DNA damage. 4-OHEN was found to be an estrogen of nanomolar potency in cell culture using a luciferase reporter assay and, using a chromatin immunoprecipitation assay, was found to activate ER{alpha} binding to estrogen-responsive genes in MCF-7 cells. DNA damage was measured in cells by comparing ER{alpha}(+) versus ER{alpha}(-) cells and 4-OHEN versus menadione, a reactive oxygen species (ROS)-generating, but non-estrogenic, quinone. 4-OHEN selectively induced DNA damage in ER{alpha}(+) cells, whereas menadione-induced damage was not dependent on cellular ER status. The rate of 4-OHEN-induced DNA damage was significantly enhanced in ER{alpha}(+) cells, whereas ER status had no effect on the rate of menadione-induced damage. Imaging of ROS induced by 4-OHEN showed accumulation selective for the nucleus of ER{alpha}(+) cells within 5 min, whereas in ER{alpha}(-) or menadione-treated cells, no selectivity was observed. These data support ER{alpha} acting as a Trojan horse concentrating 4-OHEN in the nucleus to accelerate the rate of ROS generation and thereby amplify DNA damage. The Trojan horse mechanism may be of general importance beyond estrogen genotoxins.

Received for publication October 14, 2008. Revision received January 20, 2009.

* This work was supported, in whole or in part, by National Institutes of Health Grant CA130037 (to J. L. B.). 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.

1 To whom correspondence may be addressed: 833 S. Wood St., Chicago, IL 60612-7231. Fax: 312-996-7107; E-mail: judyb{at}uic.edu. 2 To whom correspondence may be addressed: 833 S. Wood St., Chicago, IL 60612-7231. Fax: 312-996-7107; E-mail: thatcher{at}uic.edu.

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Aryl Hydrocarbon Receptor Facilitates DNA Strand Breaks and 8-Oxo-2'-deoxyguanosine Formation by the Aldo-Keto Reductase Product Benzo[a]pyrene-7,8-dione.
J.-H. Park, D. Mangal, A. J. Frey, R. G. Harvey, I. A. Blair, and T. M. Penning (2009)
J. Biol. Chem. 284, 29725-29734
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882