title: Enhanced epithelial to mesenchymal transition (EMT) and upregulated MYC in ectopic lesions contribute independently to endometriosis.
abstract: BACKGROUND
  Epithelial to mesenchymal transition (EMT) is a process in which epithelial cells lose polarity and cell-to-cell contacts and acquire the migratory and invasive abilities of mesenchymal cells. These abilities are thought to be prerequisites for the establishment of endometriotic lesions. A hallmark of EMT is the functional loss of E-cadherin (CDH1) expression in epithelial cells. TWIST1, a transcription factor that represses E-cadherin transcription, is among the EMT inducers. SNAIL, a zinc-finger transcription factor, and its close relative SLUG have similar properties to TWIST1 and are thus also EMT inducers. MYC, which is upregulated by estrogens in the uterus by an estrogen response cis-acting element (ERE) in its promoter, is associated with proliferation in endometriosis. The role of EMT and proliferation in the pathogenesis of endometriosis was evaluated by analyzing TWIST1, CDH1 and MYC expression.
  
  
  METHODS
  CDH1, TWIST1, SNAIL and SLUG mRNA expression was analyzed by qRT-PCR from 47 controls and 74 patients with endometriosis. Approximately 42 ectopic and 62 eutopic endometrial tissues, of which 30 were matched samples, were collected during the same surgical procedure. We evaluated TWIST1 and MYC protein expression by immunohistochemistry (IHC) in the epithelial and stromal tissue of 69 eutopic and 90 ectopic endometrium samples, of which 49 matched samples were analyzed from the same patient. Concordant expression of TWIST1/SNAIL/SLUG and CDH1 but also of TWIST1 and MYC was analyzed.
  
  
  RESULTS
  We found that TWIST1, SNAIL and SLUG are overexpressed (p < 0.001, p = 0.016 and p < 0.001) in endometriosis, while CDH1 expression was concordantly reduced in these samples (p < 0.001). Similar to TWIST1, the epithelial expression of MYC was also significantly enhanced in ectopic endometrium compared to eutopic tissues (p = 0.008). We found exclusive expression of either TWIST1 or MYC in the same samples (p = 0.003).
  
  
  CONCLUSIONS
  Epithelial TWIST1 is overexpressed in endometriosis and may contribute to the formation of endometriotic lesions by inducing epithelial to mesenchymal transition, as CDH1 was reduced in ectopic lesions. We found exclusive expression of either TWIST1 or MYC in the same samples, indicating that EMT and proliferation contribute independently of each other to the formation of endometriotic lesions.
authors.affiliation: Department of Obstetrics and Gynecology, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, 1090, Austria. katharina.proestling@meduniwien.ac.at.
authors.forename: Katharina
authors.initials: K
authors.lastname: Proestling
authors.affiliation: Department of Pathology, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, 1090, Austria. peter.birner@meduniwien.ac.at.
authors.forename: Peter
authors.initials: P
authors.lastname: Birner
authors.affiliation: Department of Obstetrics and Gynecology, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, 1090, Austria. susanne.gamperl@meduniwien.ac.at.
authors.forename: Susanne
authors.initials: S
authors.lastname: Gamperl
authors.affiliation: Department of Obstetrics and Gynecology, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, 1090, Austria. nadine.nirtl@meduniwien.ac.at.
authors.forename: Nadine
authors.initials: N
authors.lastname: Nirtl
authors.affiliation: Department of Obstetrics and Gynecology, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, 1090, Austria. erika.marton@meduniwien.ac.at.
authors.forename: Erika
authors.initials: E
authors.lastname: Marton
authors.affiliation: Department of Obstetrics and Gynecology, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, 1090, Austria. guelen.yerlikaya@meduniwien.ac.at.
authors.forename: Gülen
authors.initials: G
authors.lastname: Yerlikaya
authors.affiliation: Department of Obstetrics and Gynecology, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, 1090, Austria. rene.wenzl@meduniwien.ac.at.
authors.forename: Rene
authors.initials: R
authors.lastname: Wenzl
authors.affiliation: Department of Obstetrics and Gynecology, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, 1090, Austria. berthold.streubel@meduniwien.ac.at.
authors.forename: Berthold
authors.initials: B
authors.lastname: Streubel
authors.affiliation: Department of Obstetrics and Gynecology, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, 1090, Austria. heinrich.husslein@meduniwien.ac.at.|Department of Obstetrics and Gynecology, St. Michael's Hospital, University of Toronto, 30 Bond street, Toronto, Ontorio, M5B 1 W8, Canada. heinrich.husslein@meduniwien.ac.at.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Husslein
mesh_terms: D000328:Adult; D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D004715:Endometriosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004717:Endometrium / Q000378:metabolism / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005260:Female; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; C489427:MYC protein, human; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; C103173:TWIST1 protein, human; D014157:Transcription Factors; D051879:Twist-Related Protein 1