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Profiling of Estrogen-regulated MicroRNAs in Breast Cancer Cells
Published on: February 21, 2014
Estrogen receptor-mediated regulation of oxidative stress and DNA damage in breast cancer
James A Mobley1, Robert W Brueggemeier
1Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
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.
Insights
Estrogen exposure increases breast cancer cells' susceptibility to DNA damage by impairing their antioxidant defenses. This estrogen receptor-mediated effect highlights a potential mechanism in breast neoplasia development.
Area of Science:
- Endocrinology
- Molecular Biology
- Cancer Research
Background:
- Estrogens are linked to breast and gynecologic cancers, potentially through reactive oxygen species (ROS) formation and receptor-mediated pathways.
- Estrogen-induced oxidative DNA damage, like 8-oxo-2'-deoxyguanosine, suggests oxidative stress involvement in breast neoplasia initiation and progression.
Purpose of the Study:
- To investigate the impact of 17beta-estradiol (E2) on antioxidant status and peroxide-induced DNA damage sensitivity in estrogen receptor alpha (ER-alpha)-positive and -negative breast cancer cells.
- To elucidate the role of ER-alpha in mediating estrogen's effects on cellular redox state and DNA damage.
Main Methods:
- Treatment of ER-alpha-positive MCF-7 and ER-alpha-negative MDA-MB-231 cells with 10 nM 17beta-estradiol (E2).
- Measurement of changes in antioxidant enzyme activities (catalase, glutathione peroxidase, superoxide dismutases, glucose-6-phosphate dehydrogenase) and total glutathione levels.
- Assessment of cellular sensitivity to peroxide-induced DNA damage.
- Evaluation of the effects of the anti-estrogen tamoxifen.
Main Results:
- E2 treatment significantly decreased peroxide metabolism, catalase activity, and total glutathione levels in MCF-7 cells.
- These changes in MCF-7 cells correlated with increased sensitivity to peroxide-induced DNA damage.
- Estrogen-induced effects were reversed by tamoxifen and were absent in MDA-MB-231 cells, indicating an ER-mediated mechanism.
- E2 also increased glutathione peroxidase, superoxide dismutases, and glucose-6-phosphate dehydrogenase activities in MCF-7 cells.
Conclusions:
- Estrogen receptor alpha (ER-alpha) mediates the effects of 17beta-estradiol (E2) on cellular antioxidant status in breast cancer cells.
- E2 induces an increase in sensitivity to oxidative DNA damage via an ER-mediated pathway, potentially explaining in vivo pro-oxidant effects.
- Targeting ER-mediated antioxidant modulation could be a strategy in breast cancer prevention or treatment.
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