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 effectiv, 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 long-term goal of our research is to understand the molecular pathogenesis of uterine leiomyomas. Dysregulated PI3K/AKT pathway leading to the activation of mTOR has been suggested to play an essential role in the pathogenesis of leiomyomas. Our preliminary data suggest that GPR10, a GPCR normally silenced in the periphery by the tumor suppressor REST/ NRSF, is near ubiquitously over-expressed human leiomyomas. Further, REST protein is dramatically reduced in leiomyomas. Crucial to the current project, the activation of GPR10, or the loss of REST is suggested to trigger PI3K/AKT signaling and tumor cell proliferation. We hypothesize that the loss of REST leads to GPR10 expression in leiomyomas and this aberrant gene expression functionally promotes cell proliferation contributing to the pathogenesis of uterine fibroids. The current project will establish the functional role that the loss of REST has on the pathogenesis of uterine fibroids using in vitro methods and novel in vivo genetic models.
Functional loss of the repressor protein REST in the myometrium leads to the over-expression of GPR10 and to the activation of PI3K/ AKT - mTOR pathways. The project will establish a mechanistic relationship between the loss of REST and uterine fibroid pathogenesis using in vitro methods and novel in vivo models. The project advances our knowledge of signaling pathways that initiate the pathogenesis of leiomyomas.
| McWilliams, Michelle M; Chennathukuzhi, Vargheese M (2017) Recent Advances in Uterine Fibroid Etiology. Semin Reprod Med 35:181-189 |
