title: Progesterone inhibits epithelial-to-mesenchymal transition in endometrial cancer.
abstract: BACKGROUND
  Every year approximately 74,000 women die of endometrial cancer, mainly due to recurrent or metastatic disease. The presence of tumor infiltrating lymphocytes (TILs) as well as progesterone receptor (PR) positivity has been correlated with improved prognosis. This study describes two mechanisms by which progesterone inhibits metastatic spread of endometrial cancer: by stimulating T-cell infiltration and by inhibiting epithelial-to-mesenchymal cell transition (EMT).
  
  
  RESULTS
  Paraffin sections from patients with (n = 9) or without (n = 9) progressive endometrial cancer (recurrent or metastatic disease) were assessed for the presence of CD4+ (helper), CD8+ (cytotoxic) and Foxp3+ (regulatory) T-lymphocytes and PR expression. Progressive disease was observed to be associated with significant loss of TILs and loss of PR expression. Frozen tumor samples, used for genome-wide expression analysis, showed significant regulation of pathways involved in immunesurveillance, EMT and metastasis. For a number of genes, such as CXCL14, DKK1, DKK4, PEG10 and WIF1, quantitive RT-PCR was performed to verify up- or downregulation in progressive disease. To corroborate the role of progesterone in regulating invasion, Ishikawa (IK) endometrial cancer cell lines stably transfected with PRA (IKPRA), PRB (IKPRB) and PRA+PRB (IKPRAB) were cultured in presence/absence of progesterone (MPA) and used for genome-wide expression analysis, Boyden- and wound healing migration assays, and IHC for known EMT markers. IKPRB and IKPRAB cell lines showed MPA induced inhibition of migration and loss of the mesenchymal marker vimentin at the invasive front of the wound healing assay. Furthermore, pathway analysis of significantly MPA regulated genes showed significant down regulation of important pathways involved in EMT, immunesuppression and metastasis: such as IL6-, TGF-β and Wnt/β-catenin signaling.
  
  
  CONCLUSIONS
  Intact progesterone signaling in non-progressive endometrial cancer seems to be an important factor stimulating immunosurveilance and inhibiting transition from an epithelial to a more mesenchymal, more invasive phenotype.
authors.affiliation: Department of Obstetrics and Gynaecology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands. p.vanderhorst@erasmusmc.nl
authors.forename: Paul H
authors.initials: PH
authors.lastname: van der Horst
authors.forename: Yongyi
authors.initials: Y
authors.lastname: Wang
authors.forename: Ingrid
authors.initials: I
authors.lastname: Vandenput
authors.forename: Liesbeth C
authors.initials: LC
authors.lastname: Kühne
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Ewing
authors.forename: Wilfred F J
authors.initials: WF
authors.lastname: van Ijcken
authors.forename: Marten
authors.initials: M
authors.lastname: van der Zee
authors.forename: Frederic
authors.initials: F
authors.lastname: Amant
authors.forename: Curt W
authors.initials: CW
authors.lastname: Burger
authors.forename: Leen J
authors.initials: LJ
authors.lastname: Blok
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D018450:Disease Progression; D016889:Endometrial Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D023281:Genomics; D006801:Humans; D008875:Middle Aged; D011374:Progesterone / Q000494:pharmacology*; D011980:Receptors, Progesterone / Q000378:metabolism; D012189:Retrospective Studies; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D011980:Receptors, Progesterone; D011374:Progesterone