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Functional Implications of Antiestrogen Induction of Quinone Reductase: Inhibition of Estrogen-Induced Deoxyribonucleic Acid Damage

Department of Pharmacology (N.R.B., M.M.M.) and Institute of Pathology (G.P., M.A.S.), Case Western Reserve University School of Medicine, Cleveland, Ohio 44106; and Department of Pathology (D.J.T.), University of Virginia Medical School, Charlottesville, Virginia 22908-0214

Address all correspondence and requests for reprints to: Dr. Monica M. Montano, Ph.D., Case Western Reserve University School of Medicine, Department of Pharmacology, H. G. Wood Building W307, 2109 Adelbert Road, Cleveland, Ohio 44106. E-mail: mxm126{at}po.cwru.edu.

Recent studies have shown that the antiestrogens tamoxifen and raloxifene may protect against breast cancer, presumably because of a blockade of estrogen receptor (ER)-mediated transcription. Another possible explanation is that antiestrogen-liganded ER transcriptionally induces genes that are protective against cancer. We previously reported that antiestrogen-liganded ERß transcriptionally activates the major detoxifying enzyme quinone reductase (QR) [NAD(P)H:quinone oxidoreductase]. It has been established that metabolites of estrogen, termed catecholestrogens, can form DNA adducts and cause oxidative DNA damage. We hypothesize that QR inhibits estrogen-induced DNA damage by detoxification of reactive catecholestrogens. We report here that physiological concentrations of 17ß-estradiol cause oxidative DNA damage, as measured by levels of 8- hydroxydeoxyguanine, in ER-positive MCF7 breast cancer cells, MDA-MB-231 breast cancer cells (ER negative/ERß positive) and nontumorigenic MCF10A breast epithelial cells (very low ER), which is dependent on estrogen metabolism. Estrogen-induced 8-hydroxydeoxyguanine was inversely correlated to QR and ERß levels and was followed by downstream induction of the DNA repair enzyme XPA. Trans-hydroxytamoxifen, raloxifene, and the pure antiestrogen ICI-182,780 protected against estradiol-mediated damage in breast cancer cells containing ERß. This is most likely due to the ability of these antiestrogens to activate expression of QR via ERß. We conclude that up-regulation of QR, either by overexpression or induction by tamoxifen, can protect breast cells against oxidative DNA damage caused by estrogen metabolites, representing a possible novel mechanism of tamoxifen prevention against breast cancer.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  ERβ

Ligands:   17β-Estradiol  |  4-Hydroxytamoxifen  |  Raloxifene

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