Progesterone Inhibits Endometrial Cancer Invasiveness by Inhibiting the TGFβ Pathway

Increased expression of TGF beta 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 TGF beta. The goal of this study was to characterize the effect of progesterone on TGF beta signaling pathway components and on TGF beta-induced protumorigenic activities in endometrial cancer cell lines. Progesterone significantly decreased expression of three TGFb isoforms at 72 hours after treatment except for TGF beta 2 in HEC-1B and TGF beta 3 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 TGF beta receptors in HEC-1B cells and all but TGF beta R1 in Ishikawa cells. Progesterone reduced TGF beta R3 expression in RL-95 cells at 72 hours, but TGF beta R1 and beta R2 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 TGF beta 1-induced cancer cell viability and invasion, which was accompanied by increased E-cadherin and decreased vimentin expression. An inhibitor of TGF beta RI blocked TGF beta 1-induced effects on cell viability and invasion and attenuated antitumor effects of progesterone. These results suggest that downregulation of TGF beta signaling is a key mechanism underlying progesterone inhibition of endometrial cancer growth. (C) 2014 AACR.