Despite laudable recent progress in the identification of key genetic events crucial to inherited breast carcinogenesis, there is a clear lack of understanding regarding the widely hypothesized multi-step genetic events that are critical in the initiation and progression of this common, most often sporadic, and sometimes fatal cancer. Genetic analysis of sporadic breast tumors, including genome wide gene amplificationand loss of heterozygosity (LOH) studies, strongly supports the hypothesis that alterations in multiple interacting growth regulatory genes are critical in breast carcinogenesis. Characterization of the various specific alterations is necessary to understand their interrelated roles in breast carcinogenesis and their potential roles in other solid tumor malignancies. A greater understanding of the molecular basis of cancer iwll ultimately facilitate improved medical management of the disease. Specifically, increased understanding of critical genetic mechanisms should lead to improved diagnostic testing, prognostic testing, prognostic testing, and development of effective therapeutic modalities. The chief goal of this research proposal is to characterize a putative tumor suppressor gene that has been localized to a 3 cM interstitial region of chromosome 17q. Distal to and distinct from BRCA1, by tumor deletion mapping of sporadic breast tumors in our laboratory. Our hypothesis is that this putative 17q25 gene may act as a tumor suppressor in the progression of sporadic invasive ductal carcinomas. Functional analyses of mammary carcinomas by others have demonstrated that transfection of 17q25 and 17p material into a wild type p53 breast cancer cell line alters the growth and phenotype of the cell line and negates tumorigenicity in mice. Non-random cytogenetic translocations of 17q25 have also been identified in primary breast tumors. Additional studies have demonstrated that this region of chromosome 17 may also harbor a gene(s) involved in other solid tumors including ovarian and esophageal neoplasms. Our continued efforts to isolate and characterize the putative gene(s) will focus on: 1) Continued fine tumor deletion mapping studies both in breast tumors and other tumor types, 2) Linkage analysis of this genetic region in non-BRCA1 or -BRCA2 breast cancer kindreds, 3) Construction of a physical map with development of a YAC/P1/cosmid contig spanning the smallest region containing the putative tumor suppressor gene, 4) Isolation of candidate gene sequences using a variety of strategies including exon amplificatin techniques and direct cDNA selection methods, and 5) Analysis of candidate genes and elucidation of their role in breast carcinogenesis.
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