Genomic and Genetic Analysis of Hepatic Tumor Promotion

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DESCRIPTION (provided by applicant): Male mice are more susceptible than females to spontaneous liver cancer and to the induction of liver tumors by a wide variety of carcinogens. This sex difference is a consequence of the opposing effects of sex hormones on hepatocarcinogenesis: androgens promote, and ovarian hormones inhibit, the development of preneoplastic lesions, However, a significant subset of the chemicals found to induce liver tumors in mice by the National Toxicology Program are preferentially active in females. Recent work from our laboratory has led to the identification of a specific locus on Chromosome 17, Hcfl, that abrogates the inhibitory effect of the female hormonal environment on liver tumor development. We will test the hypothesis that Hcfl and chemicals that specifically induce liver tumors in female mice induce common signaling pathways during promotion of hepatocarcinogenesis. First, female-specific hepatocarcinogens, including 5,5-diphenylhydantoin, safrole, and Fumonisin BI, and agents active as promoters in both sexes, such as HBB and WY-14,643, will be compared for their promoting activities in female C57BL/6J and congenic Hcfl mice. Hepatic mRNA from animals treated for 12 weeks with these agents will be analyzed using liver-specific, cDNA microarrays in order to elucidate common patterns of altered gene expression. Second, phenotypically distinct classes of preneoplastic lesions promoted by these agents will be compared by microarray analysis of cDNA prepared from tissue isolated by laser capture micro-dissection. Finally, the molecular identity of the Hcfl locus will be determined by positional cloning.