Progesterone inhibits endometrial cancer invasiveness by inhibiting the TGFß pathway.

ABSTRACT

Increased expression of TGFß 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 TGFß. The goal of this study was to characterize the effect of progesterone on TGFß signaling pathway components and on TGFß-induced protumorigenic activities in endometrial cancer cell lines. Progesterone significantly decreased expression of three TGFß isoforms at 72 hours after treatment except for TGFß2 in HEC-1B and TGFß3 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 TGFß receptors in HEC-1B cells and all but TGFßR1 in Ishikawa cells. Progesterone reduced TGFßR3 expression in RL-95 cells at 72 hours, but TGFßR1 and ßR2 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 TGFß1-induced cancer cell viability and invasion, which was accompanied by increased E-cadherin and decreased vimentin expression. An inhibitor of TGFßRI blocked TGFß1-induced effects on cell viability and invasion and attenuated antitumor effects of progesterone. These results suggest that downregulation of TGFß signaling is a key mechanism underlying progesterone inhibition of endometrial cancer growth.