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

Mol Endocrinol. 2003 Jul;17(7):1344-55. doi: 10.1210/me.2002-0382. Epub 2003 Apr 24.

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

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

Substances

  • 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)