SAT-003 Prolactin Is Expressed in Uterine Leiomyomas and May Promote Their Growth

Uterine leiomyomas, commonly referred to as fibroids, are benign, estrogen sensitive smooth muscle tumors that occur in the myometrium of the uterine wall. Leiomyomas are common, as it is estimated that 60% of reproductive-aged women are affected, and 80% of women develop leiomyomas during their lifetime. In fact, uterine leiomyomas are the leading cause of abnormal menstrual bleeding or menstrual pain, as well as the number one reason for hysterectomy. Novel treatment options are necessary as current treatments are limited to anti-estrogen therapy or hysterectomy. Estrogen is known to have an effect on the etiology of leiomyomas, but little is known about the proliferative roles of other hormones in leiomyomas. One hormone of interest is prolactin (PRL) which is primarily secreted from the pituitary to regulate lactation, but has been linked to proliferation in breast cancer, perhaps via local prolactin production in breast tissue. With this background, we examined local PRL production and its effects on leiomyomas. RNA isolation and quantitative PCR of human leiomyoma samples (n=20) relative to adjacent myometrium in the same patients confirmed significant expression of both PRL (p= 0.0028) and dopamine receptor D2, a known regulator of PRL production in the pituitary (p<0.0001), with no difference in prolactin receptor expression. Using both immunohistochemistry and immunofluorescence of human leiomyomas samples, we find increased prolactin expression in leiomyomas when compared to adjacent myometrium or control uteri. These results suggest that leiomyomas contain cells producing PRL, which in turn may promote signaling in smooth muscle leiomyoma cells to regulate proliferation. Accordingly, we find that PRL robustly activates STAT5 and MAPK signaling in the rat leiomyoma cell line ELT3. Functional assays were also conducted to evaluate the ability of PRL to induce migration, invasion and proliferation of ELT3 cells. Together, our findings suggest that local prolactin production in leiomyomas may promote their growth, migration, invasion and proliferation. It is possible that this local production is mediated by the dopamine receptor D2. Thus, anti-PRL therapy or dopamine receptor D2 modulation may prove useful in treating this prevalent and often debilitating disease.