Regulation of the vascular endothelial growth factor and growth by estrogen and antiestrogens through Efp in Ishikawa endometrial carcinoma cells

Vascular endothelial growth factor (VEGF) is a potent angiogenic and prognostic factor for endometrial cancer. Estrogen and tamoxifen are considered to be associated with increasing risk of endometrial adenocarcinoma. To investigate the effects and mechanisms of estrogen and antiestrogens (tamoxifen and raloxifene) on the growth of endometrial carcinoma cells in vitro, we performed growth studies of estradiol and antiestrogens on estrogen receptor positive Ishikawa cells. The effects of estradiol and antiestrogens on the induction of VEGF and estrogen-responsive finger protein (Efp) were measured by QRT-PCR and ELISA or Western blotting. The siRNA method was used to investigate the action of Efp on Ishikawa cell growth and the induction of VEGF by estradiol and antiestrogens. Estradiol and tamoxifen induced Ishikawa cell proliferation and expression of Efp and VEGF on mRNA and protein levels, while raloxifene did not. The effects of estradiol were partly or almost completely inhibited by tamoxifen and raloxifene. When the Efp expression was suppressed by siRNA, the cell growth was decreased with estradiol treatment, and other actions of estradiol and tamoxifen such as induction of VEGF were decreased. These results demonstrate that estradiol and tamoxifen may regulate the growth of endometrial carcinoma cells by stimulating VEGF production through Efp, and the effects of estradiol could be amplified by Efp. This study suggest that tamoxifen acts as an agonist-antagonist, and raloxifene acts as an antagonist of estrogen in Ishikawa cells in vitro.