The major goal of this project is to add to our knowledge of the etiology of carcinoma of the pancreas in order to provide a basis for prevention of the disease. Carcinoma of the pancreas ranks fifth among cancers as a cause of death in the United States, and is seldom diagnosed early enough to be treatable. Three strains of transgenic mice will be used in studies of experimental pancreatic carcinogenesis and carcinoma. A breeding colony of transgenic mice bearing the elastase promoter-SV40-early antigen, (ELSV), and the elastase promoter-myc (EL-myc) gene construct will provide animals for in vivo studies and tumors for molecular genetic studies to identify additional genetic changes associated with focal neoplastic transformation and progression in the pancreas. It is generally accepted that multiple genetic changes have occurred in cells during the development of a malignant phenotype. The transgene construct endows all pancreatic cells in these mice with one such change, but the focal (clonal) development of carcinomas suggests that additional changes of oncogene or tumor suppressor gene function will be found in the carcinomas. The tumors will be examined for selected mutations and altered expression of oncogenes that have been associated with pancreatic carcinomas in humans or in other experimental models. Initial studies will focus on detecting mutations of the ras oncogene using the polymerase chain reaction and sequence analysis to recognize mutations. This will be followed by evaluation of p53 expression and mutation. Selected dietary additives such as butylated hydroxyanisole and chymostatin will be evaluated for the ability to inhibit or promote the development of carcinomas in transgenic mice during """"""""lifetime"""""""" in vivo studies. The mechanism of effect of hormones including estrogen and androgen on the development of pancreatic carcinomas will be evaluated by assessing their effect on T-antigen expression in the pancreas prior to the development of cancers and on the formation and growth of transformed clones within the pancreas in longer term studies using morphometric analysis.
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