Understanding expression and signaling of sex hormone receptors in brain cancers

About This Grant

PROJECT SUMMARY There is significant evidence of cancer-type specific patterns of sex hormone receptor expression and signaling in many central nervous system (CNS) tumors, often correlating with their high sex-specificity. This supports the hypothesis that sex hormone receptors play tumorigenic and pathologic roles across many CNS cancers. However, their mechanistic functions in CNS tumors remain largely unknown. This proposal seeks to address these knowledge gaps in 2 of these cancers: meningioma and glioblastoma (GBM). In Aim 1, I explore the mechanism underlying progesterone receptor (PR) expression and signaling in meningiomas, the most common primary intracranial tumors. Meningiomas are 2.7 times more common in females than in males, can arise in the setting of exogenous female hormone therapy, and 70% express high levels PR, suggesting female sex hormones may drive meningioma tumorigenesis. Using human meningioma xenografts in mice treated with clinically relevant doses of synthetic progestins, I developed a model of female sex hormone-driven meningioma. The data presented in this application suggest progestins induce PR expression, increase tumor growth, and reduce survival through a positive feedback mechanism that requires progesterone membrane component 1 (PGRMC1), a non-classical hormone receptor with pathologic roles in breast and endometrial cancers. The central hypothesis of my doctoral dissertation project is that progestin ligand activates PGRMC1 to drive expression of PR in meningioma through regulation of NFB transcriptional activity, and that PR drives meningioma growth through cytoplasmic activation of MAPK signaling and transcriptional activation of TNFSF11, TGFA, and IRS2. Through the remainder of my graduate work I will (i) validate the pathway through which PGRMC1 drives PR expression through ChIP-QPCR, luciferase reporter, and loss-of-function validation models, (ii) identify hormonal cofactors involved in PGRMC1 signaling, (iii) validate the roles of PR downstream targets in driving growth and proliferation in meningioma through gain- and loss-of-function models, and (iv) incorporate human proteomic data to define expression levels of proteins implicated in PR and PGRMC1 signaling pathways in human patients. In Aim 2, I outline the proposed direction of my postdoctoral studies, the characterization of sex hormone signaling pathways in GBM. The most malignant primary brain tumors in adults, GBM are often marked by high expression of androgen and estrogen receptors, yet limited and often contradictory functional data for these receptors in GBM has impeded the development of sex hormone-targeted therapeutics. For this project, I plan to (i) perform integrated proteomic and phospho-proteomic characterization of hormone signaling networks in GBM, (ii) characterize and mechanistically validate the pathways through which sex hormone signaling influences GBM pathology, and (iii) develop combination therapies targeting these signaling axes. Taken together, these projects will integrate genetics, biochemistry, and proteomics to characterize therapeutically vulnerable signaling pathways in meningioma and GBM.