REST-MED12 Pathways in the Regulation of Estrogen - Progesterone Sensitivity in Uterine Leiomyoma

Project Summary/Abstract Uterine fibroids (leiomyomas) are benign smooth muscle cell (SMC) tumors of the myometrium. Leiomyomas represent the most frequent clinical indication for hysterectomy that often prematurely ends a woman's reproductive capability. In the year 2010, the estimated annual cost of uterine fibroid tumors in the United States was $5.9-34.4 billion. Yet in spite of this, there are currently no approved drugs that can provide effective, long-term treatment for these tumors. There is an unmet need to identify molecular targets for the development of therapies to treat uterine fibroids. The major goal of the project is to understand the role of REST and MED12, tumor suppressors functionally lost or mutated in uterine fibroids, in the molecular pathogenesis of uterine leiomyomas. The two participating laboratories have made important discoveries on the role of REST and MED12 in the pathogenesis of UL utilizing genetically modified mouse models for the loss of REST and for the most common missense mutation in the MED12 gene respectively. Crucially, data from Rest conditional knockout in the mouse uterus showed that the loss of REST expression leads to UL tumor formation, increased estrogen receptor 1 (ESR1) pathway activation and revealed a direct role for REST in regulating progesterone receptor function in the uterus. Additionally, UL tumorigenesis in the Med12 mutant mouse model is uniquely dependent on both progesterone and estrogen. Importantly, REST, an epigenetic regulator, is known to interact with MED12. The current proposal brings together two of the most critical tumor suppressor molecules in UL for a comprehensive investigation into their role in the dysregulation of estrogen – progesterone pathways in uterine fibroids. The project will define molecular hallmarks for the development of tissue selective progesterone and estrogen receptor modulators in the future.