The overall goal of our research program is to identify and understand the mechanisms of action of specificgenes that modulate risk for cancer development in inbred mice. These studies will provide insights into thesignaling pathways critical for hepatocarcinogenesis in mice, as well as models for understanding the actionof modifier genes for cancer risk in humans. We have identified the Hcs7 locus as the major determinant ofthe high susceptibility of C3H/HeJ (C3H) and CBA/J mice to liver tumor induction relative to C57BL/6J (B6)mice and demonstrated that this gene is located on distal Chromosome 1. We also found that one of thesusceptibility genes, Hcf2, carried by sensitive C57BR/cdJ (BR) mice mapped to the same region.Comparative studies of hepatocarcinogenesis in C3H, BR, and B6 mice by our group and othersdemonstrate that the Hcs7 and Hcf2 loci act cell autonomously to control the growth or development ofpreneoplastic hepatic lesions, but the molecular identities of these genes are still unknown. We havelocalized the Hcs7gene to a 6.4 Mbp interval on Chromosome 1. We propose to elucidate the mechanismsby which Hcs7 modulates liver cancer risk through the following approaches. First, we will determine themolecular identity of Hcs7 through positional cloning. We will prioritize candidate genes based on mappingto sub-centiMorgan resolution, analysis of shared SIMP haplotypes for relevant strains, hepatic geneexpression, and functional criteria. Candidates will then be tested by transgenesis using Bacterial ArtificialChromosome (BAG) clones or gene replacement. Second, we will elucidate the biological basis for Hcs7modulation of cancer risk by comparing Hcs7 BAG transgenic or allelic replacement strains to controlparental or congenic mice for phenotypes related to hepatocarcinogenesis. Finally, we will determine themolecular mechanisms by which Hcs7 acts through analysis of hepatic gene expression in BAG transgenicand congenic mice, and characterization of mice carrying germ-line or liver-specific null mutations in Hcs7.
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