Uterine leiomyoma are both highly prevalent and symptomatic. These tumors play a significant role in miscarriage, infertility, preterm labor, heavy menstrual periods, 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 pregnancy loss 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. Cells that make up uterine leiomyomas possess characteristics similar to both the progenitor myocyte and fibroblasts. Retinoic acid regulates cellular differentiation in a wide array of tissues. We have previously demonstrated that cells that make up leiomyomas control molecular expression to minimize retinoic acid concentration. What is unknown, however, is how retinoic acid exposure would alter the molecular and structural phenotype of human uterine leiomyomas, and what retinoic acid deprivation would do to patient-matched normal myometrium. In order to address this question, we have generated immortalized cell lines from human tissue to test hypotheses on the functional role of retinoic acid on uterine leiomyomas. We hypothesize that control of retinoic acid exposure regulates the differentiation pattern unique to leiomyomas. Our two specific aims are: (1) to characterize the exposure and metabolism of retinoic acid in human surgical specimens and tissue cultures of leiomyoma and myometrium, and (2) to determine the role of retinoic acid on molecular expression levels of genes specific to human uterine leiomyomas using immortalized leiomyoma and myometrial cell lines. By the completion of the proposed studies, we will understand the molecular alterations in the retinoic acid pathway of leiomyomas, and understand the impact of retinoic acid exposure on molecular expression patterns. Characterized differential gene expression between leiomyoma and normal myometrium can identify targets that can be exploited therapeutically.
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 differentiation, providing the ground-work for future therapies to minimize or eliminate leiomyomas and their associated morbidity.
