Pancreatic cancer is the fifth most common cause of cancer mortality in the United States (American Cancer Society, 1987). The vast majority are considered to be ductal in origin. Currently there is no adequate animal model for pancreatic duct cell adenocarcinoma. The overall aim of their proposal will be go develop a transgenic animal model for this neoplasm. We will identify enhancer sequences that modulated pancreatic duct cell specific gene expression, link them to the sequence for SV40 T- antigen, and utilize them to make a transgenic animal model. The CA II gene will be utilized for identification of the duct cell specific enhancer sequences since immunohistochemical evidence suggests that CA II is expressed in human duct cells, but not in acinar or islet cells. CA II was selected because it corresponds to the only duct cell specific gene that has been cloned. In order to identify sequences important in the regulation of CA II gene expression in pancreatic due cells, we will prepare a series of constructs composed of deletion mutants of the human and mouse CA II gene linked to the chloramphenicol acetyl transferase (CAT) gene which will be utilized as a reported sequence. These constructs will be introduced into pancreatic cell lines known to produce CA II. The effects of these different sequences on expression will be determined. The constructs which enhance expression of CAT will be introduced into mice, and those animals expressing CAT will be analyzed for tissue specific expression. When duct cell specific enhancer sequences are identified in the CA II gene region, we will develop a duct cell tumor modern by introducing the constructs containing the enhancer sequences linked to the SV40 T-antigen sequence into mice, to generate transgenic animals. A lack of progress in the understanding of pancreas cancer is in part due to the limited number of pancreatic tumor specimens available for biological research. The development of an adequate animal model is even more important when one considers these limitations.
