Uterine fibroids (leiomyomata uteri) are the most common tumors in the female reproductive tract. Some estimates indicate that more than 50% of American women have uterine fibroids. Additionally, there is a significant disparity in the incidence of fibroids since African-American women are 2-3 times more likely to develop fibroids. These tumors can be very painful and are a leading cause of infertility in women. Also, because these tumors can become very large, and although the uterus is indispensable for mammalian reproduction, they remain the main reason for hysterectomies in the US. Despite the healthcare burden caused by uterine fibroids, their etiology and pathophysiology are unknown. We have developed mutant mice in which nuclear ?-catenin signaling has been specifically induced in reproductive tract tissues. Normally, mice do not develop fibroids;however, these mutant mice develop smooth muscle tumors in their uteri with 100% penetrance by 8 weeks of age. These tumors exhibit characteristics of human fibroids by histological and immunohistochemical criteria. ?-Catenin, a well-known downstream effector of Wnt signaling, induces organ and tissue malformations and tumor development following dysregulation of its activity. The mice also express higher levels of mTor, as observed in the Tsc2-mutant Eker rat fibroid model and in approximately 50% of human fibroids, suggesting that mTor activation may be a common pathway in leiomyoma development. We will investigate this mouse model further, placing particular emphasis on the regulation of mTor gene expression and activity for comparison with other mutant mouse models lacking myometrial Lkb1, the gene mutated in patients with Peutz-Jeghers Syndrome, and Tsc1, both of which also induce mTor activity and induce uterine fibroids as shown in our preliminary results. We propose to investigate the intracellular mechanisms and pathways affected by dysregulated Wnt/?-catenin in our unique mouse model that induce mTor activity for comparison with Lkb1- and Tsc2-deleted uteri. To better understand the etiology and pathogenesis of fibroids, we will study the molecular mechanisms controlling fibrosis in the mutant myometrial cells such as cell polarity, extracellular matrix deposition, and myometrial differentiation. We will determine which characteristics of the mouse models most closely resemble human leiomyomas and are best suited for preclinical studies. Lastly, we will determine whether disrupted Wnt/?-catenin signaling contributes to human leiomyoma development. The results from the studies in this proposal will provide new insights into the etiology and progression of these tumors, as well as provide the rationale for investigating therapies targeting the mechanisms involved in leiomyoma development and progression.
Uterine fibroids affect approximately 50% of American women during their reproductive years and are a significant source of pelvic pain, abnormal uterine bleeding, and infertility. Despite the major health care burden posed by uterine fibroids, very little is known about their cause or the best treatment strategies. As a result, if the symptoms are severe enough, patients can be managed by surgical intervention. The overall aims of the proposed studies are to understand the underlying causes of uterine fibroid development and growth and to develop new therapeutic options that could offer a safer alternative for treating this disease.
|Kaneko-Tarui, Tomoko; Commandeur, Arno E; Patterson, Amanda L et al. (2014) Hyperplasia and fibrosis in mice with conditional loss of the TSC2 tumor suppressor in Müllerian duct mesenchyme-derived myometria. Mol Hum Reprod 20:1126-34|