Abstract 3467: Progesterone inhibits endometrial cancer growth and invasiveness by modulating the TGF-ß pathway

Objectives: Our group has shown previously that progesterone may exert a chemoprotective effect against endometrial cancer through modulation of TGF-β signaling and concomitant activation of apoptosis in the endometrium. In addition, it has been shown that increased expression of TGF-β isoforms in human endometrial cancer correlates with decreased survival and poor prognosis. These data suggest that the TGF-β pathway may be an attractive target for chemoprevention strategies. The goal of this study was to further characterize the effect of progesterone on TGF-β signaling pathway components (TGF-β isoform and Smads) and on TGF- β-induced pro-tumorigenic activities in endometrial cancer cell lines. Methods: The expression levels of TGF-β ligands (TGF-β1, TGF-β2 and TGF-β3), TGF-β receptors (TGF-βR1, TGF-βR2, and TGF-βR3) and SMADs (pSMAD2/3, SMAD2/3 and SMAD-4) were determined by immunoblotting in HEC-1B endometrial cancer cells exposed to progesterone for 24, 72 and 120 h. Proliferation and cellular invasion assays were used to access the functional effects of progestin exposure in the HEC-1B and Ishikawa endometrial cancer cell lines. Results: A marked decrease in TGF-β1and TGF-β3 expression was observed at 72 h after treatment with progesterone. Expression of TGF-βR1, TGF-βR2, SMAD2/3 and pSMAD2/3 were substantially reduced at 72 h while levels of SMAD4 and TGF-β2 expression were reduced at 120 h following progesterone. TGF-βR3 expression levels were not affected by any treatment at any time point. Furthermore, TGF-β1-induced cancer cell proliferation and invasion was effectively inhibited by progesterone. Cellular proliferation and invasion were significantly reduced by progestin compared to controls even in the presence of exogenous TGF-β. Conclusions: These results suggest that the down-regulation of TGF-β signaling may be a key mechanism underlying progestin inhibition of endometrial carcinogenesis. Citation Format: Amber A. Bokhari, Laura R. Lee, Dewayne Raboteau, Chad A. Hamilton, George L. Maxwell, Jane M. Turbov, Larry G. Thaete, Gustavo C. Rodriguez, Viqar Syed. Progesterone inhibits endometrial cancer growth and invasiveness by modulating the TGF-ß pathway. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3467. doi:10.1158/1538-7445.AM2014-3467