The objectives of the proposed research plan are an investigation of the role of selenium, as inorganic selenite, in the prevention of 7,12-dimethylbenzanthracene- (DMBA) induced mouse mammary tumorigenesis. Previous experiments have demonstrated that dietary selenium (0.5-2.0 ppm) significantly inhibits DMBA-induced mouse mammary cancer. Additionally, the early stages of the neoplastic transformation, the induction and/or expression of mammary preneoplasias, appear to be the most sensitive stage to selenium-mediated inhibition. In the proposed research, in vivo transplantation experiments and in vitro model systems will be used to investigate the effect of selenium on the growth kinetics of non-neoplastic mammary epithelial cell populations. The in vivo experiments will examine the effects of selenium on the expression of the preneoplastic phenotype. Addtionally, the effect of selenium on the DNA labeling index and growth fraction will be examined using 3H-thymidine as a label for DNA. The in vitro experiments will examine the effect of selenium on the cell cycle kinetics of 2 mammary epithelial cell lines which show a biphasic growth response to selenium. Additionally, the localization and incorporation of 75-selenium into the nucleus and nuclear subfractions will be examined using cell fractionation, DNA isolation and high pressure liquid chromatography techniques. At the end of 3 years, these experiments should provide evidence to support or deny the hypothesis that one of the principal mechanisms of selenium-mediated inhibition is acting by inhibiting DNA synthesis of preneoplastically-transformed mammary epithelial cells.
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