Abstract
Abstract Abstract: Mutation of the tumor suppressor gene MEN1 causes both human inherited and somatic tumors in multiple endocrine tumors. Dissection of mechanism on MEN1 tumor model will shed light on tumor biology and the targeting therapies on neuroendocrine tumors lacking Men1. Loss of tumor suppressor menin may be tumorigenic because it leads to decreased histone H3 lysine 4 trimethylation and therefore decreased expression of specific genes such as CDKN1B. Reversing the tumorigenesis caused by menin deficiency might therefore be achieved by inhibition of histone H3 lysine 4 demethylation. Rbp2 (also known as KDM5A) is an excellent candidate for such a demethylase because loss of the Rbp2 gene leads to increased expression of CDKN1B. Using a tissue-specific knockout approach, I have disrupted Men1 alone or both Men1 and Rbp2 in mouse pancreatic islets through RIP-Cre transgene (RIP = “rat insulin promoter”) and have observed that loss of Rbp2 dramatically inhibits tumor growth in Men1-deficient islets. Histological assays have found that 100 percent of Men1f/f RIP-Cre mice (13 out of 13) at 10 months old or older harbor tumors of the pancreatic islets, whereas only 7 out of 21 Men1f/f; Rbp2f/f RIP-Cre mice contain tumors or large hyperplastic islets. Furthermore, Inactivation of Rbp2 extends the life span of Men1-deficient mice. The median survival age of Men1f/f RIP-Cre mice in this cohort is 313 days, the median survival age of Men1f/f; Rbp2f/f RIP-Cre (n=72) is 486 days (p<0.0001). In addition, a number of targets shared by both Men1 and Rbp2 have been identified via expression profiling. Studies from this project may provide insight to the cause of endocrine tumors and may develop a molecular target for treatment of endocrine tumors and the MEN-1 syndrome through modulation of histone methylation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 62. doi:10.1158/1538-7445.AM2011-62
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