title: Progesterone inhibits endometrial cancer invasiveness by inhibiting the TGFβ pathway.
abstract: Increased expression of TGFβ 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 TGFβ. The goal of this study was to characterize the effect of progesterone on TGFβ signaling pathway components and on TGFβ-induced protumorigenic activities in endometrial cancer cell lines. Progesterone significantly decreased expression of three TGFβ isoforms at 72 hours after treatment except for TGFβ2 in HEC-1B and TGFβ3 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 TGFβ receptors in HEC-1B cells and all but TGFβR1 in Ishikawa cells. Progesterone reduced TGFβR3 expression in RL-95 cells at 72 hours, but TGFβR1 and βR2 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 TGFβ1-induced cancer cell viability and invasion, which was accompanied by increased E-cadherin and decreased vimentin expression. An inhibitor of TGFβRI blocked TGFβ1-induced effects on cell viability and invasion and attenuated antitumor effects of progesterone. These results suggest that downregulation of TGFβ signaling is a key mechanism underlying progesterone inhibition of endometrial cancer growth.
authors: Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
authors: Amber A
authors: AA
authors: Bokhari
authors: Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
authors: Laura R
authors: LR
authors: Lee
authors: Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
authors: Dewayne
authors: D
authors: Raboteau
authors: Division of Gynecologic Oncology, and Gynecologic Cancer Translational Research Center of Excellence, Walter Reed National Military Medical Center, Bethesda, Maryland.
authors: Chad A
authors: CA
authors: Hamilton
authors: Department of Obstetrics and Gynecology and Women's Health Integrated Research Center, Inova Fairfax Hospital, Falls Church, Virginia.
authors: George L
authors: GL
authors: Maxwell
authors: Division of Gynecologic Oncology, North Shore University Health System, University of Chicago, Evanston, Illinois.
authors: Gustavo C
authors: GC
authors: Rodriguez
authors: Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, Maryland. Department of Molecular and Cell Biology, Uniformed Services University of the Health Sciences, Bethesda, Maryland. viqar.syed@usuhs.edu.
authors: Viqar
authors: V
authors: Syed
mesh_terms: D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D003470:Culture Media; D017077:Culture Media, Conditioned / Q000737:chemistry; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D008024:Ligands; D008856:Microscopy, Fluorescence; D009361:Neoplasm Invasiveness; D011374:Progesterone / Q000378:metabolism*; D015398:Signal Transduction; D051901:Smad4 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D003470:Culture Media; D017077:Culture Media, Conditioned; D008024:Ligands; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014746:Vimentin; D011374:Progesterone