Uterine leiomyomas (also known as uterine fibroids) are benign smooth muscle tumors of the myometrium that are thought to be present in up to 70% of women. Symptoms associated with clinically significant fibroids include, pelvic pain, excessive and/or painful menstruation, anemia, recurrent pregnancy loss and infertility. Uterine fibroids are the leading cause of hysterectomies, over 200,000 annually. Despite the prevalence of uterine leiomyomas and the importance of the uterus for a woman's reproductive capacity, little is known about the etiology and pathogenesis of the disease. Furthermore, because of the gap in knowledge surrounding leiomyoma development and progression, advancement in therapeutics to prevent or treat the disease is hindered. The myometrium is proposed to contain adult stem cells that participate in growth/expansion and damage repair of the tissue during the menstrual/estrous cycle, pregnancy and post-partum uterine involution. Likewise, leiomyomas are thought to arise from a single mutated myometrial stem/progenitor cell;however the factors and mechanisms that cause this change are unknown. WNT/?-Catenin signaling is well known for its role in regulating stem cell function and in carcinogenesis. Recent reports suggest that improper WNT/?- Catenin signaling might contribute to leiomyoma formation and growth. The goal of this proposal is to determine the contribution of myometrial stem/progenitor cells with dysregulated ?-Catenin activity to leiomyoma development. In this proposal an emphasis is placed on studying leiomyoma tumor formation rather than progression or maintenance of established tumors. The first specific aim is to isolate myometrial stem/progenitor cells by enriching using surface markers and verify their stem cell activity in vitro and in vivo. In the second specific aim, a constitutively active (CA) form of ?-Catenin will be expressed in myometrial stem/progenitor cells to study the impact on leiomyoma development. These cells will be used in xenotranplantation experiments to study early leiomyoma tumor formation and will also be used to determine genes and signaling pathways affected by CA ?-Catenin, which is a transcriptional coactivator. The work proposed here, to study the role of myometrial stem/progenitor cells and dysregulated ?-Catenin signaling in leiomyoma development, will provide important insight into the etiology and pathogenesis of the disease and may lead to new therapeutic tools to better manage uterine leiomyomas.
Understanding the mechanisms of uterine leiomyoma (fibroid) formation is crucial to uncovering methods to prevent and treat the disease, which affects a substantial number of women in the United States. Existing evidence suggests a role for dysregulated adult stem/progenitor cells in fibroid growth and development. The proposed research will study the contribution of stem/progenitor cells specifically to the development of uterine fibroids with the goal of uncovering the mechanisms and disrupted pathways involved in the process.