1 Revised Manuscript – Carcin-2003-00012 Estrogen Receptor-mediated Regulation of Oxidative Stress and DNA Damage in Breast Cancer

D ow nloaded from 2 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-positive MCF-7 cells and estrogen receptor alpha-negative MDA-MB-231 cells with 10 nM 17β-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 metaboliz