The objectives of this research project are to identify and characterize genes whose expressions are altered during selenium-mediated inhibition of rat mammary tumorigenesis. This objective will be approached by isolating and characterizing differentially expressed mRNA in selenium-treated normal mammary gland and atypical ductal hyperplasias using differential display PCR methodology. Subsequent characterization of the cDNAs will involve comparative mRNA expression by Northern blotting, nucleotide sequencing of full-length message RNA, functional analysis by transfection studies, protein production and antibody development. The use of selenium compounds which represent different categories; i.e., alkylselenocysteines, triphenylselenonium, lipophilic selenoniums, will provide information on the specificity of selenium effects on mammary cells. The experiments will be performed on two general cell population models.
In SPECIFIC AIM 1, selenium-modified gene expression in chemical carcinogen-induced intraductal proliferations will be examined. As conditions are optimized for utilizing DD-PCR on rat mammary tissues, specific aim 2 will be attempted.
In SPECIFIC AIM 2, the effects of selenium on gene expression in chemical carcinogen-treated normal mammary will be examined. This experiment might identify selenium effects on normal mammary cells which influence the growth of the transformed mammary epithelial cells. The selenium compounds to be evaluated are the 2nd and 3rd generation compounds developed in the previous years of research of the Program Project. The candidate genes generated by these experiments will be evaluated in the assays utilized in PROJECT 3. The molecular mechanisms underlying selenium chemopreventive activities are not understood and molecular markers related to selenium effects on cells are rare. It is anticipated that this experimental approach will provide new molecular markers and insight into selenium chemopreventive activities and/or selenium effects on cell function.
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