Deletions at chromosome 8p22 are very frequent in some of the most common human cancers, including those of the prostate, breast and esophagus. During the past five years we have made an effort to clone genes frequently involved in human epithelial tumors and have been able to clone the gene at 3p, FHIT, that is involved in the pathogenesis of some of the most common human cancers, including lung cancer, and is mutated more frequently than the p53 gene in human malignancies. In this application, it is I proposed to identify and characterize the gene at 8p22 that is altered in prostate, breast and esophageal cancer. The PI has already identified a region of 1.5Mb that is frequently involved in loss of heterozygosity at 8p22 in several epithelial malignanciesas well as several genes in this region. Analysis of these genes for mutations and/or altered expression in human epithelial cancers indicated that one of them, Fez1, is altered in epithelial tumors. The Fez1 gene encodes a leucine zipper protein with a domain similar to the DNA binding domain of the camp responsive activating-transcription factor 5. We have also demonstrated that Fez1 interacts with EFgamma. We propose to investigate the role of the Fez1 gene in human cancer and we will: 1) determine whether Fez1 is a classic tumor suppressor gene by introducing it into prostate, breast and esophageal cancer derived cell lines to establish whether the transfected tumor cells fail to form tumors in immunosuppressed mice, 2) clone and sequence genes encoding Fez1 partner proteins to gain information concerning the function of Fez1 3) knock out the Fez1 gene in the mouse to assess the consequences of Fez1 loss of function in the development of tumors and 4) to investigate large panels of prostate, breast and esophageal cancers for the expression of Fez1 to determine whether Fez1 loss of function has prognostic significance. We will also determine whether Fez1 loss of function makes cancer cells more resistant to chemotherapeutic drugs. Finally, we will determine whether FHIT and Fez1 are collaborating tumor suppressor genes
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