The short arm of human chromosome 3 in the region 3p21.3 is deleted in many cancers including lung cancer which is the cause of 40,000 deaths in the U.S. each year. A fragment of chromosome 3 from this region suppresses tumor formation of A9 mouse fibrosarcoma cells in a nude mouse assay. Furthermore, this same fragment of chromosome 3 changes the response of A9 cells to chemotherapeutic drugs from apoptosis to growth arrest. This study is designed to identify the gene inducing tumor suppression in A9 and to determine whether it is the same gene imparting the differential response to chemotherapeutic drugs. The cDNA which suppresses tumor growth of mouse A9 fibrosarcoma cells will be identified using an inducible expression system. The candidate cDNA will be tested to determine if it is the same gene which gives a differential response to chemotherapeutic drugs. The cDNA which induces tumor suppression and differential drug response in mouse A9 cells will be tested for these effects in human tumor cells including small call lung cancer. The inactivation of this gene in human tumors will be explored by both mutation analysis and by methylation assays. The mechanism of action of the tumor suppressor gene and the basis of the switch from apoptosis to growth arrest will be determined relating this gene to other genes in apoptotic pathways. This study will define a gene which already has been implicated in a number of cancers by deletion and define its functioning in normal cells and during tumorigenesis. Status of this gene in a tumor may provide clues about that tumor's response to chemotherapeutic drugs.
