Estrogen receptor-mediated regulation of oxidative stress and DNA damage in breast cancer

TLDR: This is the first report indicating that E2 is capable of inducing an increase in sensitivity to oxidative DNA damage through an ER-mediated mechanism, and may explain some of the estrogen-induced pro-oxidant effects previously reported in vivo.

Abstract: Estrogens have been implicated to be complete carcinogens in breast and gynecologic tissues. Possible mechanisms may include differential metabolism with subsequent formation of reactive oxygen species and/or a receptor-mediated pathway, which may also involve indirect modulation of intracellular redox state. Estrogen-mediated oxidative DNA damage in mammary gland epithelia includes the induction of 8-oxo-2'-deoxyguanosine, both in vitro and in vivo, thereby suggesting a role for oxidative stress in the initiation and/or progression of breast neoplasia. In order to study this phenomenon, we have treated estrogen receptor alpha (ER-alpha)-positive MCF-7 cells and ER-alpha-negative MDA-MB-231 cells with 10 nM 17beta-estradiol (E2), while measuring changes in antioxidant status and sensitivity to DNA damage by peroxide. Treatment of MCF-7 cells with E2 resulted in a marked decrease in the ability for these cells to metabolize peroxide, which paralleled a decrease in catalase activity and total glutathione levels. These observations also correlated with an increased sensitivity to peroxide-induced DNA damage. The estrogen-induced effects were all opposed by the anti-estrogen tamoxifen. In addition, the estrogen-mediated down regulation of peroxide metabolism, catalase activity, and sensitivity to DNA damage were not observed in the MDA-MB-231 cell line. Treatment of MCF-7 cells with E2 also resulted in increased glutathione peroxidase, superoxide dismutases (I) and (II) and glucose-6-phosphate dehydrogenase activities. Therefore, in this breast cancer model antioxidant status is modulated through the actions of the ER. The data may explain some of the estrogen-induced pro-oxidant effects previously reported in vivo. In addition, this is the first report indicating that E2 is capable of inducing an increase in sensitivity to oxidative DNA damage through an ER-mediated mechanism.