1,25-Dihydroxyvitamin D3 Regulates Expression of Sex Steroid Receptors in Human Uterine Fibroid Cells

Context: Uterine fibroids (UFs) are the most common benign tumors in premenopausal women. In this study, we evaluated the effects of 1,25-dihydroxyvitamin D3 [1,25(OH)(2)D3] for the treatment of UFs. Objective: To determine the role of 1,25(OH)(2)D3 on the expression of sex steroid receptors in human UF cells. Design: Human UFs and their adjacent myometrium were analyzed for expression of estrogen receptor (ER)-alpha, progesterone receptor (PR)-A, and PR-B, as well as members of the steroid receptor coactivator (SRC) family. Immortalized human uterine fibroid (human uterine leiomyoma [HuLM]) cells were treated with 1,25(OH)(2)D3 and assayed for the expression and localization of the aforementioned receptors and SRCs using Western blot, immunohistochemistry, immunofluorescence, and immunoprecipitation assays. Main Outcome Measures: We discovered a correlation between reduced levels of vitamin D receptor . VDR) and increased levels of ER-alpha, PR-A, and PR-B in these tissues. Weevaluated the effects of 1,25(OH)(2)D3 on the regulation of the aforementioned sex steroid receptors. Results: We observed an inverse correlation between the up-regulated ER-alpha, PR-A, and PR-B and expression of VDR in UFs. Treatment with 1,25(OH)(2)D3 significantly decreased levels of ER-alpha, PR-A, and PR-B, as well as SRCs in HuLM cells (P < .05). In contrast, 1,25(OH)(2)D3 self-induced its own VDR, which resulted in an induction of VDR-retinoidXreceptor-alpha complex in HuLM cells. Together, these results suggest that 1,25(OH)(2)D3 functions as an antagonist of sex steroid hormone receptors in HuLM cells. Conclusions: 1,25(OH)(2)D3 functions as a potent antiestrogenic/antiprogesteronic agent that may have utility as a novel therapeutic option for UF.