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 tumor cell. Ultimately this will improve both prognostic outcomes and treatment of regimens. A novel technology, based on the Cre-loxP recombinase system which enables large regions of the mouse genome to be deleted has been developed. A series of mice with deletions (each several megabases) which in sum cover the entire distal half of mouse chromosome 11, will be generated by the Deletion Core. This region of the mouse genome, containing an estimated 2,000 genes, is syntenic with human chromosome 17. Although three tumor suppressor genes have been localized to this chromosome (NF1, p53 and BRCA1), loss of heterozygosity studies strongly suggest that there are several other tumor suppressor genes on this chromosome which are mutated at a high frequency in sporadic tumors. Tumors suppressor genes are difficult to identify because two mutational events are required to disrupt the function of the gene in a diploid cell. Fibroblasts isolated from mice with these deficiencies have a single copy of each gene in the region of the deficiency. A genetic screen will be employed to identify these tumor suppressor genes, based on the hypothesis that cells which loose the remaining copy of the tumor suppressor gene can be identified in a large pool of cells since they transform in vitro. Transformation foci will be induced by pro-viral tagging in primary embryonic fibroblasts isolated from mice with these deficiencies. The pro-viral tag will facilitate the direct molecular identification of the tumor suppressor gene which causes transformation in these cell lines.
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