The Genetic Components of Susceptibility to Breast Cancer in the Rat

The rat is an extremely valuable model for studies of inherited susceptibility to breast cancer because the characteristics of rat mammary cancer and human breast cancer are so similar. There are now several rat models for studying sensitivity versus resistance, or cell autonomy versus non-cell-autonomy, for spontaneous and induced mammary cancers. It is known that the tumor-resistant Cop [20, 21] and WKy [8] strains carry dominant resistance genes that inhibit both spontaneous and induced mammary tumors. The WF and SD strains are known to carry dominant sensitivity genes that appear to increase susceptibility to induced but not spontaneous mammary tumors. The presence of both resistance and sensitivity genes in the Cop strain is intriguing, and provides a unique model for studying the interactions of both types of genes. It appears that the resistance genes together are at least partially dominant over the sensitivity gene in this model since the F1 rats develop only a few tumors. Yet another strain, the F344, has an intermediate sensitivity and has been shown to carry neither sensitivity or resistance genes. Thus, all these models and data indicate that sensitivity genes are not necessary for the development of mammary tumors, and neither are they sufficient. However, loss of resistance gene function is necessary but is not sufficient for mammary tumor development. Studies have shown that the sensitivity and resistance genes act directly within the mammary epithelial cells rather than globally in the rat. The products of these genes also do not appear to act at early steps in the carcinogenic process because there have been no observed effects of these genes on carcinogen metabolism or DNA adduct formation. It would appear that these genes act at later stages of mammary carcinogenesis. Identification and isolation of these genes should aid our understanding of the inherited components of human breast cancer. With the increasing availability of genetic markers and large-insert libraries for the rat genome, genetic and physical mapping studies are now a reality for the genes involved in mammary carcinogenesis of the rat. Such studies have already revealed the multigenic nature of this cancer, supporting the idea that the limited penetrance of BRCA1 and BRCA2 in human breast cancer is due to loci that modify the effects of the sensitivity genes. Assuming that human homologues of the Mcs genes exist, cloning the genes and defining the human homologues may provide a way to identify the risk for breast cancer development in women. Analysis of the function of such genes may also lead to the development of new drugs for chemoprevention and/or therapy of this lethal disease.