This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Meningiomas comprise 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% are atypical and 3-5% are malignant. Complete surgical resection is the treatment of choice for benign meningiomas. Surgical resection is often difficult since approximately one-half of benign intracranial meningiomas arise in the skull base. For skull base meningiomas the surgical complication rate can be as high as 30 to 40% even in expert hands. The female to male incidence ratio in adults is 2:1 for intracranial tumors and 10:1 for spinal tumors, while no such sex difference exists for meningiomas in children. Therefore, the female sex steroid hormones progesterone and b-estradiol are suspected factors in meningioma tumorigenesis. However, no mechanisms have been demonstrated for female sex hormones in meningioma 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 data indicate that a number of steroid responsive genes are differentially expressed between meningiomas and normal meninges. We also found that steroid hormones and their antagonists can alter the growth of meningioma cells and that histone deacetylase inhibitors induce a decrease of meningioma cell growth in culture. Our long-term goal is to develop strategies to prevent or slow meningioma tumor growth that can serve as alternatives or adjuncts to surgery. The central hypotheses of this study are 1) that meningioma tumorigenesis is driven in part by actions of female steroid hormones and 2) that the tumorrigenesis may be mediated in part by progesterone and estrogen receptor containing chromatin-modifying complexes. We propose to test our hypothesis by pursuing the following three specific aims: 1) To treat meningioma cells with progesterone or 17b-estradiol and assess the expression of several genes 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 of meningioma cells in vitro and on expression of genes that are differentially expressed between meningiomas and normal meninges. 3) To determine whether the promoters of the differentially regulated genes in specific aim 1 and 2 are bound by progesterone receptor, estrogen receptor, ETS2, or the histone acetyltransferase p300.
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