title: Lack of estrogen receptor-α is associated with epithelial-mesenchymal transition and PI3K alterations in endometrial carcinoma.
abstract: OBJECTIVE
  We hypothesized that estrogen receptor-α (ER-α) status in endometrial carcinomas, associated with poor prognosis, is reflected in transcriptional signatures suggesting targets for new therapy.
  
  
  METHODS
  Endometrial carcinoma samples in a primary investigation cohort (n = 76) and three independent validation cohorts (n = 155/286/111) were analyzed through integrated molecular profiling. Biomarkers were assessed by immunohistochemistry (IHC), DNA oligonucleotide microarray, quantitative PCR (qPCR), single-nucleotide polymorphism (SNP) array, and Sanger sequencing in the cohorts, annotated for comprehensive histopathologic and clinical data, including follow-up.
  
  
  RESULTS
  ER-α immunohistochemical staining was strongly associated with mRNA expression of the receptor gene (ESR1) and patient survival (both P < 0.001). ER-α negativity associated with activation of genes involved in Wnt-, Sonic Hedgehog-, and TGF-β signaling in the investigation cohort, indicating epithelial-mesenchymal transition (EMT). The association between low ER-α and EMT was validated in three independent datasets. Furthermore, phosphoinositide 3-kinase (PI3K) and mTOR inhibitors were among the top-ranked drug signatures negatively correlated with the ER-α-negative tumors. Low ER-α was significantly associated with PIK3CA amplifications but not mutations. Also, low ER-α was correlated to high expression of Stathmin, a marker associated with PTEN loss, and a high PI3K activation signature.
  
  
  CONCLUSIONS
  Lack of ER-α in endometrial cancer is associated with EMT and reduced survival. We present a rationale for investigating ER-α's potential to predict response to PI3K/mTOR inhibitors in clinical trials and also suggest EMT inhibitors to ER-α-negative endometrial carcinomas.
authors: Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway. elisabeth.wik@med.uib.no
authors: Elisabeth
authors: E
authors: Wik
authors: Maria B
authors: MB
authors: Ræder
authors: Camilla
authors: C
authors: Krakstad
authors: Jone
authors: J
authors: Trovik
authors: Even
authors: E
authors: Birkeland
authors: Erling A
authors: EA
authors: Hoivik
authors: Siv
authors: S
authors: Mjos
authors: Henrica M J
authors: HM
authors: Werner
authors: Monica
authors: M
authors: Mannelqvist
authors: Ingunn M
authors: IM
authors: Stefansson
authors: Anne M
authors: AM
authors: Oyan
authors: Karl H
authors: KH
authors: Kalland
authors: Lars A
authors: LA
authors: Akslen
authors: Helga B
authors: HB
authors: Salvesen
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D058534:Class I Phosphatidylinositol 3-Kinases; D016889:Endometrial Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D006801:Humans; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011379:Prognosis; D011446:Prospective Studies; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D047628:Estrogen Receptor alpha; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; C506487:ESR1 protein, human; C484760:PIK3CA protein, human