Affiliation:
1. Department of Obstetrics and Gynecology, Yamagata University Faculty of Medicine, Yamagata 990-9585, Japan
Abstract
AbstractWe examined the molecular mechanisms of the antiestrogenic effects of clomiphene citrate (CC) in the endometrium using two types of cell lines, Ishikawa and EM-E6/E7/hTERT cells. CC or ICI182780 inhibited 17β-estradiol (E2)-induced endometrial cell proliferation and transcriptional activation of the estrogen response element (ERE) gene. We directly visualized the ligand-estrogen receptor (ER)α interaction using green fluorescent protein (GFP)-tagged ERα in a single living cell. Whereas E2 changed the nuclear localization of GFP-ERα to a punctate distribution within 5 min, CC or ICI182780 changed the slower and less mobilization of GFP-ERα compared with E2. Pretreatment with CC or ICI182780 partly prevented the E2-induced nuclear redistribution of GFP-ERα. Fluorescence recovery after photobleaching revealed that GFP-ERα mobility treated with E2 was more rapid than that treated by CC or ICI182780. As coactivator recruitment to the ER is essential for ER-dependent transcription, we examined the interaction between ERα and steroid receptor coactivator-1 (SRC-1). The complex formation between ERα and SRC-1 was significantly increased by E2 but was prevented in the presence of CC or ICI182780 by coimmunoprecipitation. Moreover, the E2-induced colocalization of GFP-ERα and SRC-1 was prevented in the presence of CC or ICI182780 according to an immunofluorescence assay. We also observed that the reduction of SRC-1 using small interfering RNA for SRC-1 resulted in the inhibition of E2-induced cell proliferation and transcriptional activation of the ERE gene. Collectively, these results suggest that CC may inhibit E2-induced endometrial epithelial cell proliferation and ERE transactivation by inhibiting the recruitment of SRC-1 to ERα.
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