Functional implications of antiestrogen induction of quinone reductase: inhibition of estrogen-induced deoxyribonucleic acid damage.

Abstract

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 ERbeta 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 17beta-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 (ERalpha negative/ERbeta 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 ERbeta 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 ERbeta. This is most likely due to the ability of these antiestrogens to activate expression of QR via ERbeta. 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.

• Authors: Nicole R Bianco, George Perry, Mark A Smith, Dennis J Templeton, Monica M Montano
• Journal: Molecular endocrinology (Baltimore, Md.) (Mol Endocrinol) Vol. 17 Issue 7 Pg. 1344-55 (Jul 2003) ISSN: 0888-8809 [Print] United States
• PMID: 12714703 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• DNA-Binding Proteins
• Estrogen Receptor Modulators
• Estrogen Receptor alpha
• Estrogen Receptor beta
• Estrogens
• Receptors, Estrogen
• XPA protein, human
• Xeroderma Pigmentosum Group A Protein
• Tamoxifen
• afimoxifene
• Fulvestrant
• Raloxifene Hydrochloride
• Estradiol
• Guanine
• 8-oxo-7,8-dihydrodeoxyguanine
• 8-Hydroxy-2'-Deoxyguanosine
• NAD(P)H Dehydrogenase (Quinone)

Topics

• 8-Hydroxy-2'-Deoxyguanosine (analogs & derivatives)
• Breast Neoplasms (enzymology, genetics)
• DNA Damage (drug effects, physiology)
• DNA Repair (drug effects, physiology)
• DNA-Binding Proteins (drug effects, metabolism)
• Enzyme Activation (drug effects)
• Epithelial Cells (metabolism)
• Estradiol (analogs & derivatives, metabolism, pharmacology)
• Estrogen Receptor Modulators (pharmacology)
• Estrogen Receptor alpha
• Estrogen Receptor beta
• Estrogens (metabolism, pharmacology)
• Female
• Fulvestrant
• Guanine (analogs & derivatives, metabolism)
• Humans
• NAD(P)H Dehydrogenase (Quinone) (drug effects, metabolism)
• Oxidative Stress
• Raloxifene Hydrochloride (pharmacology)
• Receptors, Estrogen (drug effects, genetics, metabolism)
• Tamoxifen (analogs & derivatives, pharmacology)
• Tumor Cells, Cultured
• Xeroderma Pigmentosum Group A Protein