We have chosen as a model system to study a locus that has exhibited the potential to alter susceptibility to various types of tumors. The agouti locus found on chromosome 2 of the mouse was first identified by its effects on coat color. Mice carrying the wild-type alleles at the agouti locus exhibit a coat color pattern of hairs that are banded black-yellow-black. Mutations at the agouti locus have shown a variation in coat color from complete yellow to complete black. Several of the numerous agouti mutations that have been identified over the years appear to influence normal and neoplastic growth. Their effects have been shown to result in increased susceptibility to spontaneous hepatomas in males, spontaneous and induced mammary tumors in females, spontaneous and induced pulmonary tumors, and induced skin tumors. In addition, recent evidence has pointed to the agouti locus playing a role in tumor progression. The previous findings have pointed to the involvement of the agouti locus in susceptibility, since in mice carrying single agouti mutations but expressing variable coat color phenotypes, the incidence of tumors correlates with the amount of phaeomelanin present m coat hairs. In addition, the agouti locus provides a link between obesity and cancer susceptibility, since in mice carrying these dominant agouti mutations, there is also a correlation between the degree of obesity and the amount of phaeomelanin present in coat hairs. This proposal plans to identify and characterize the gene(s) which are altered in these mutants, understand their function, and use this information to establish transgenic model systems for studying tumor susceptibility and obesity.
