Genetically Modified Mice in Cancer Research

The laboratory mouse offers tremendous opportunities for studies on the genetic basis of cancer. No other model system is so easily and widely used to test the effect of potentially oncogenic mutations in a living animal. Mouse strains differ extraordinarily in their innate susceptibilty to various forms of cancer (see Jackson Laboratories website: http://tumor.informatics.jax.org/ straingrid.html ). The reasons for these differences are thought to lie in allelic variation in cancer susceptibility genes between strains. Breeding experiments have allowed researchers to localize some of these susceptibility genes regionally (1 ,2 ). The molecular identification of these susceptibility genes has proved elusive. However, cancer research has yielded many other types of cancer genes whose function has been tested using the power to manipulate the mouse germline. A large number of oncogenes have been discovered by studying oncogenic retroviruses, from transfection of tumor DNAs into mouse embryo fibroblast cell lines, and by molecular analyses of human tumors. Tumor suppressor genes have been discovered from linkage studies and positional cloning in human families segregating highly penetrant predisposition to specific tumor types (3 ). Mouse transgenesis has proved to be the most powerful and widely used system for the in vivo analysis of the function of cancer genes discovered by these methods. Several excellent reviews have been written on this subject (4 –6 ). In this chapter, I briefly describe the history of mouse transgenesis in cancer research, some widely utilized models, new technologies, and future directions for mouse genetics in cancer research.