Genetic identification of Mcs-1, a rat mammary carcinoma suppressor gene

Women have inherited differences in their susceptibility to breast cancer, but the genes underlying this variation are difficult to identify. We have approached the problem of identifying breast cancer susceptibility genes by using a rat model. Inbred rat strains display differential susceptibilities to mammary carcinogenesis; the Copenhagen (COP) rat is resistant, while the Wistar-Furth (WF) rat is susceptible to induction of mammary tumors by 7,12-dimethylbenz[a]anthracene. Genetic breeding studies have shown that tumor resistance in the COP rat is a dominant phenotype, termed the rat mammary carcinoma suppressor trait. As a step toward defining the basis of this resistance, we undertook genetic mapping of this phenotype in a (WF x COP)F1 x WF backcross by studying a large collection of microsatellite and minisatellite polymorphisms. A total of 114 genetic markers, covering approximately 75% of the rat genome, were genotyped in the backcross progeny. A marker on rat chromosome 2 was found to show linkage to the resistance phenotype. Genetic linkage was demonstrated both in a qualitative analysis (in which rats were defined as resistant if they developed 0 tumors and sensitive if they developed two or more tumors; LOD score, 4.0) and in a quantitative trait locus analysis (in which tumor number was used as the quantitative phenotype; LOD score, 3.8). We infer the existence of a gene, Mcs-1, on rat chromosome 2 that suppresses mammary carcinogenesis.