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Inhibition of Estrogen-induced Growth of Breast Cancer by Targeting Mitochondrial Oxidants
Final rept. 14 Mar 2006-13 Mar 2009
FLORIDA INTERNATIONAL UNIV MIAMI
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We have completed all proposed research, except a part of Task 4-related to xenograft tumor experiments in nude mice. This will be completed during no-cost extension period. We observed in this study that estrogen induced redox signaling mediates proliferation and growth of MCF-7 cells exposed to estrogens. Over-expression of biological ROS scavengers MnSOD and Catalase or treatments of cells with chemical antioxidants, N-acetylcysteine NAC and ebselen, inhibits estrogen induced expression of cell cycle genes as well as prevention of estrogen-induced growth of malignant breast epithelial cells. Also, findings of this study support ROS functioning as signal molecules in E2-induced cell transformation. These findings suggest that, in addition to the estrogen receptor activity, E2-generated mitochondrial ROS may promote susceptibility to malignant transformation as well as growth of malignant breast cancer cells. Thus our results suggest 1 a new paradigm that estrogen-induced mitochondrial oxidants control the early stage of cell cycle progression and growth of breast cancer cells, 2 estrogen-induced mitochondrial oxidants control cell transformation and invasiveness of transformed cells and 3 provide the basis for the discovery of novel antioxidant-based drugs or antioxidant gene therapies for the prevention and treatment of estrogen-dependent breast cancer.
APPROVED FOR PUBLIC RELEASE