Abstract 4166: Targeted expression of the Pleomorphic adenoma gene 1 in the pancreas of mice leads to islet hyperplasia

Abstract

Abstract Pleomorphic adenoma gene 1 (PLAG1) encodes a transcription factor that is involved in several human neoplasias such as in pleomorphic adenomas of the salivary glands, lipoblastoma, hepatoblastoma and AML. The oncogenic capacity of PLAG1 has been further demonstrated in vivo in PLAG1 transgenic mice, in which the activation of the PLAG1 expression is Cre-mediated. Targeted expression of PLAG1 in the salivary gland or in the mammary gland leads to pleomorphic adenomas of the salivary glands and adenomyoepitheliomatous lesions of the mammary glands, respectively. Here, we investigated the impact of targeted PLAG1 expression in the pancreas. Pdx1-Cre-mediated targeted expression of PLAG1 in the whole pancreas, leads to islet hyperplasia. Although there was initially a balanced increase in the insulin, somatostatin and glucagon content of the pancreas, in older P1-Pdx1Cre mice the production of insulin and somatostatin far exceeded that of glucagon (82%, 275% and 9% respectively in 1 year old P1-Pdx1Cre mice as compared to littermate Pdx1-Cre mice). This was associated with hyperinsulinemia and an increased ability to dispose glucose in P1-Pdx1Cre mice, and progressive development of severe hypoglycaemia. Only 1/10 one year old mice developed a pancreatic tumor. We also investigated the consequence of overexpression of PLAG1 only in β-cells by using RIP-Cre mice. Similar to P1-Pdx1Cre mice, P1-RIPCre mice displayed islet hyperplasia, hyperinsulinemia and an increased ability to dispose glucose. Nevertheless, in contrast to P1-Pdx1Cre mice, P1-RIPCre mice stay normoglycemic and compensate for the hyperinsulinemia by the development of hepatic insulin resistance. In conclusion our data demonstrates that targeted expression of PLAG1 in the pancreas leads to islet hyperplasia rather than to pancreatic tumor formation. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4166.