FA 5 Progress Report WV-INBRE - Joan C. Edwards School of ...

Program Director/Principal Investigator (Last, First, Middle): Rankin, Gary O 45SEX STEROID HORMONES AND EPIGENETICS IN MENINGIOMAS (0038)TYPE: Research Subproject%IDeA $: 5.000% IDeA $: 174,407INVESTIGATOR, DEGREEHankins, Gerald PHDDEPARTMENTBiologyNON-HOST INSTITUTION: STATE,COUNTRYWest Virginia State University, Wv UsaTotal # human subjects expected for entire study: 0Total # human subjects enrolled to date: 0SUBPROJECT DESCRIPTIONMeningiomas comprine approximately 30% of primary central nervous system tumors in the United States,however their pathobiology is poorly understood. Over 90% of meningiomas are benign while 5% areatypical and 3-5% are malignant. Complete surgical resection is the treatment of choice for benignmeningiomas. Surgical resection is often difficult since approximately one-half of benign intracranialmeningiomas arise in the skull base. For skull base meningiomas the surgical complication rate can be ashigh as 30 to 40% even in expert hands. The female to male incidence ratio in adults is 2:1 for intracranialtumors and 10:1 for spinal tumors, while no such sex difference exists for meningiomas in children.Therefore, the female sex steroid hormones progesterone and -estradiol are suspected factors inmeningioma tumorigenesis. However, no mechanisms have been demonstrated for female sex hormonesinmeningioma formation or progression. We recently reported evidence that a steroid responsive gene,deleted in liver cancer-1 (DLC1), may function as a tumor suppressor in meningiomas. Our microarray dataindicate that a number of steroid responsive genes are differentially expressed between meningiomas andnormal meninges. We also found that steroid hormones and their antagonists can alter the growth ofmeningioma cells and that histone deacetylase inhibitors induce a decrease of meningioma cell growth inculture. Our long-term goal is to develop strategies to prevent or slow meningioma tumor growth that canserve as alternatives or adjuncts to surgery. The central hypotheses of this study are 1) that meningiomatumorigenesis is driven in part by actions of female steroid hormones and 2) that the tumorrigenesis may bemediated in part by progesterone and estrogen receptor containing chromatin-modifying complexes. Wepropose to test our hypothesis by pursuing the following three specific aims:1) To treat meningioma cells with progesterone or 17β-estradiol and assess the expression of severalgenes that are differentially regulated between meningiomas and normal meninges.2) To evaluate the effects of inhibitors of DNA methylation or histone de-acetylation on the growth ofmeningioma cells in vitro and on expression of genes that are differentially expressed betweenmeningiomas and normal meninges.3) To determine whether the promoters of the differentially regulated genes in specific aim 1 and 2 arebound by progesterone receptor, estrogen receptor, ETS2, or the histone acetyltransferase p300.1) To treat meningioma cells with progesterone or 17 -estradiol and assess the expression of severalgenes that are differentially regulated between meningiomas and normal meninges.2) To evaluate the effects of inhibitors of DNA methylation or histone de-acetylation on the growth ofmeningioma cells in vitro and on expression of genes that are differentially expressed betweenmeningiomas and normal meninges.3) To determine whether the promoters of the differentially regulated genes in specific aim 1 and 2 arebound by progesterone receptor, estrogen receptor, ETS2, or the histone acetyltransferase p300.SUBPROJECT PROGRESSDuring the past year we have focused on specific aims 1 and 2.One graduate student and an undergraduate student have focused on fibroblast growth factorsPHS 2590 (Rev. 06/09)Continuation Format Page