Cancer is a genetic disease. Identifying genes which are playing a causal role in cancer and elucidating their function will enhance our understanding of the neoplastic process. This information will improve our ability to modulate the disease by providing therapeutic opportunities based on knowledge of the genetic changes in a tumor cell. Ultimately this will improve both prognostic outcomes and treatment regimens. We have recently developed a novel technology based on the Cre-loxP recombinase system which enables large regions of the mouse genome to be deleted. We are proposing to generate a series of mice with deletions (each several megabases) which in sum cover the entire distal half of mouse chromosome 4, which represents about 2.5 percent of the genome (2500 genes). This region of the mouse genome is syntenic with human chromosome 1p, which is known to contain several tumor suppressor genes which are mutated in a variety of different tumors. A genetic screen will be employed to identify the tumor suppressor genes using these mice. This screen is based on the induction of transformation foci by pro-viral tagging in primary embryonic fibroblasts isolated from mice with these deficiencies. The pro-viral tag will facilitate the molecular identification of insertionally inactivated tumor suppressor genes in these cell lines.
