Uterine leiomyoma play a significant role in miscarriage, infertility, preterm labor, menorrhagia, pelvic pain, and urinary incontinence. Despite such dramatic symptoms, the etiology of uterine leiomyomas is marginally understood. This limited understanding has translated to limited therapeutic options. For women suffering from uterine leiomyomas who desire to maintain their fertility, major surgery is the only current option available, and recurrence is not uncommon. As a result, these women must choose between risking the demise of an otherwise healthy unborn child or risking repeat surgery, with ever-increasing likelihood of short- and long-term morbidity and mortality. Better understanding of uterine leiomyoma development would provide novel targets for medical therapy that could minimize the risk of uterine leiomyomas on pregnancy and general health while at the same time eliminating the risks associated with surgical intervention. One such medical therapy, mifepristone, decreases tumor size, although the mechanism is unclear. In preliminary studies, we have demonstrated that mifepristone regulated leiomyoma extracellular matrix (ECM) production within the cell. What is unknown, however, is whether mifepristone regulates ECM formation and can stimulate ECM dissolution in leiomyomas, and the mechanism by which ECM regulates the leiomyoma cellular phenotype. In order to address this deficit, we have produced 3-D immortalized cell lines from human leiomyoma and patient-matched myometrium and plan to characterize the impact of mifepristone treatment on ECM formation and degradation. We will also expand upon our findings of aberrant mechanotransduction on ECM production and signaling via the Rho signaling pathway by characterizing ECM production in 3-D leiomyoma cultures relative to 3-D myometrial cultures. Our two specific aims are: (1) to characterize the impact of mifepristone on ECM formation and dissolution on 3-D leiomyoma cultures, and (2) to confirm that perturbations in mechanical stress through formed ECM alter Rho/ERK signaling and increase aberrant ECM formation. By the completion of the proposed studies, we will have characterized the therapeutic impact of a clinically effective therapy (mifepristone) on 3-D leiomyoma ECM, and the impact of Rho signaling on ECM component formation. This project is innovative in that (1) it uses the only model system designed to study ECM, (2) it characterizes a clinically effective therapy, and (3) it uses a human model to study a prevalent human disease.
Uterine leiomyomas are highly prevalent and frequently symptomatic in reproductive-aged women, resulting in extensive absenteeism, increased employer cost, and a societal cost of over $8 billion per year. Not as quantifiable are the associated monetary and emotional costs with the miscarriage of otherwise healthy pregnancies as a result of leiomyomas. The studies outlined in this proposal will provide insight into leiomyoma growth, providing the ground-work for future therapies to minimize or eliminate leiomyomas and their associated morbidity.
|Malik, Minnie; Britten, Joy; Cox, Jeris et al. (2016) Gonadotropin-releasing hormone analogues inhibit leiomyoma extracellular matrix despite presence of gonadal hormones. Fertil Steril 105:214-24|