Progesterone Inhibits Endometrial Cancer Invasiveness by Inhibiting the TGFβ Pathway

Abstract

Increased expression of TGFb isoforms in human endometrial cancer correlates with decreased survival and poor prognosis. Progesterone has been shown to exert a chemoprotective effect against endometrial cancer, and previous animal models have suggested that these effects are accompanied by changes in TGFb. The goal of this study was to characterize the effect of progesterone on TGFb signaling pathway components and on TGFb-induced protumorigenic activities in endometrial cancer cell lines. Progesterone significantly decreased expression of three TGFb isoforms at 72 hours after treatment except for TGFb2 in HEC-1B and TGFb3 in Ishikawa cells. Progesterone treatment for 120 hours attenuated expression of the three isoforms in all cell lines. Progesterone exposure for 72 hours reduced expression of TGFb receptors in HEC-1B cells and all but TGFbR1 in Ishikawa cells. Progesterone reduced TGFbR3 expression in RL-95 cells at 72 hours, but TGFbR1 and bR2 expression levels were not affected by progesterone at any time point. SMAD2/3 and pSMAD2/3 were substantially reduced at 72 hours in all cell lines. SMAD4 expression was reduced in RL-95 cells at 24 hours and in HEC-1B and Ishikawa cells at 72 hours following progesterone treatment. Furthermore, progesterone effectively inhibited basal and TGFb1-induced cancer cell viability and invasion, which was accompanied by increased E-cadherin and decreased vimentin expression. An inhibitor of TGFbRI blocked TGFb1-induced effects on cell viability and invasion and attenuated antitumor effects of progesterone. These results suggest that downregulation of TGFb signaling is a key mechanism underlying progesterone inhibition of endometrial cancer growth. Cancer Prev Res; 7(10); 1045-55. Ó2014 AACR.

Nestin suppression attenuates invasive potential of endometrial cancer cells by downregulating TGF-β signaling pathway

“…Previously we have shown enhanced proliferation and invasive potential of endometrial cells in response to TGF-β1 [38]. Here we substantiated the direct interaction between Nestin and TGF-β in Nestin overexpressing cells by demonstrating a marked increase in Nestin expression which was associated with enhanced proliferation and invasive potential in response to TGF-β1 exposure.…”

“…We and others have previously shown that TGF-β signaling pathway is activated in endometrial cancer cells [22, 23, 38]. Our findings suggest that elevated levels of Nestin in endometrial cancer cells can stimulate cell proliferation and invasion by stimulating TGF-β signaling pathway.…”

Progesterone potentiates the growth inhibitory effects of calcitriol in endometrial cancer via suppression of CYP24A1

“…We previously reported that progesterone-mediated upregulation of vitamin D receptor (VDR) levels increases calcitriol-induced growth inhibition in endometrial cancer cells [9, 10]. Here, we expand upon our previous work by examining the effects of calcitriol and progesterone, both alone and in combination, on CYP24A1.…”

“…Combining a low dose of progesterone with a low dose of calcitriol, a vitamin D metabolite, might be more effective for treating endometrial cancer than higher doses of either agent alone. In vitro and in vivo studies from our laboratory and others have shown that progesterone and other chemopreventive agents enhance the antitumor effects of calcitriol [7–10]. …”

Tumor progression, metastasis, and modulators of epithelial–mesenchymal transition in endometrioid endometrial carcinoma: an update

“…Recently, progesterone was shown to inhibit basal and TGFB1 induced cancer cell viability and invasion, which was accompanied by increased E-cadherin and decreased vimentin expression (Bokhari et al 2014). Chaudhry et al (2014) observed that TGFB upregulates the expression of prostate apoptosis response-4, a tumor suppressor protein, with simultaneous induction of EMT in endometrial and cervical cancer cells.…”