Estrogen receptor regulation of quinone reductase in breast cancer: implications for estrogen-induced breast tumor growth and therapeutic uses of tamoxifen.
Antiestrogens have found widespread use in the treatment of breast cancer (reviewed in ref. 1). There is also interest in the use of tamoxifen as a preventive agent for breast cancer. However, the mechanism for the antitumor effects of antiestrogens is relatively unknown. For the most part it is thought that the basis for the anticancer action of antiestrogens is the inhibition of estradiol (E2)-stimulated tumor growth. We have observed however that antiestrogens can activate detoxifying enzymes, like quinone reductase (NQO1), which protect cells against the toxic and tumor-promoting effects of carcinogens (2). Studies characterizing the molecular mechanisms behind the regulation of NQO1 by the Estrogen Receptor (ER) support an important role of the ER in pathways regulating antioxidant defenses. Moreover these findings represent a novel mechanism through which antiestrogens function. The activation of NQO1 may contribute to the beneficial anticancer and antioxidant activity of antiestrogens in breast cancer and possibly other estrogen target tissues. It is possible that the basis for some of the anticancer action of antiestrogens is that the induction of NQO1 inhibits the genotoxic effects induced by the oxidative metabolism of estrogens.
Montano
Monica M
MM
Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44122, USA. mxm126@po.cwru.edu <mxm126@po.cwru.edu>
Bianco
Nicole R
NR
Deng
Huayun
H
Wittmann
Bryan M
BM
Chaplin
Laura C
LC
Katzenellenbogen
Benita S
BS
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000139:chemically induced / Q000188:drug therapy*; D004965:Estrogen Antagonists / Q000627:therapeutic use*; D004967:Estrogens; D006801:Humans; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000502:physiology*; D013629:Tamoxifen / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004965:Estrogen Antagonists; D004967:Estrogens; D011960:Receptors, Estrogen; D013629:Tamoxifen; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human