1,25-dihydroxyvitamin D3 regulates expression of sex steroid receptors in human uterine fibroid cells

Ayman Al-Hendy, Ayman Al‐Hendy, Michael P. Diamond, Ahmed El-Sohemy, Ahmed El‐Sohemy, Sunil K. Halder
The Journal of clinical endocrinology and metabolism · 2015 · vol. 100(4) , pp. E572–E582 · doi:10.1210/jc.2014-4011 · PMID:25625804 · PMC4399292 · W2151583120
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1,25-dihydroxyvitamin D3 treatment decreased estrogen and progesterone receptor expression in human uterine fibroid cells, suggesting it may act as an antiestrogenic/antiprogesteronic agent.

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Abstract

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)2D3] for the treatment of UFs. OBJECTIVE: To determine the role of 1,25(OH)2D3 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)-α, 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)2D3 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-α, PR-A, and PR-B in these tissues. We evaluated the effects of 1,25(OH)2D3 on the regulation of the aforementioned sex steroid receptors. RESULTS: We observed an inverse correlation between the up-regulated ER-α, PR-A, and PR-B and expression of VDR in UFs. Treatment with 1,25(OH)2D3 significantly decreased levels of ER-α, PR-A, and PR-B, as well as SRCs in HuLM cells (P < .05). In contrast, 1,25(OH)2D3 self-induced its own VDR, which resulted in an induction of VDR-retinoid X receptor-α complex in HuLM cells. Together, these results suggest that 1,25(OH)2D3 functions as an antagonist of sex steroid hormone receptors in HuLM cells. CONCLUSIONS: 1,25(OH)2D3 functions as a potent antiestrogenic/antiprogesteronic agent that may have utility as a novel therapeutic option for UF.

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MeSH descriptors

Estrogen Receptor alpha Leiomyoma Receptors, Progesterone Uterine Neoplasms Vitamin D Cell Proliferation Cell Proliferation Estrogen Receptor alpha Female Humans Leiomyoma Leiomyoma Myometrium Myometrium Myometrium Myometrium Receptors, Calcitriol Receptors, Calcitriol Receptors, Progesterone Tumor Cells, Cultured

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