GENETIC IDENTIFICATION OF MULTIPLE LOCI THAT CONTROL BREAST-CANCER SUSCEPTIBILITY IN THE RAT

We have used a rat model of induced mammary carcinomas in an effort to identify breast cancer susceptibility genes. Using genetic crosses be tween the carcinoma-resistant Copenhagen (COP) and carcinoma-sensitive Wistar-Furth rats, we have confirmed the identification of the Mcs1 l ocus that modulates tumor number. We have now also identified two addi tional loci, Mcs2 and Mcs3. These three loci map to chromosomes 2, 7, and 1, respectively, and interact additively to suppress mammary carci noma development in the COP strain. They are responsible for a major p ortion of the tumor-resistant phenotype of the COP rat. No loss of het erozygosity was observed surrounding the three loci. A fourth COP locu s, Mcs4, has also been identified on chromosome 8 and acts in contrast to increase the number of carcinomas. These results show that mammary carcinoma susceptibility in the COP rat is a polygenic trait. Interes tingly, a polymorphism in the human genomic region homologous to the r at Mcs4 region is associated with an increased breast cancer risk in A frican-American women. The isolation of the !Mcs genes may help elucid ate novel mechanisms of carcinogenesis, provide information important for human breast cancer risk estimation, and also provide unique drug discovery targets for breast cancer prevention.