title: Loss of GPER identifies new targets for therapy among a subgroup of ERα-positive endometrial cancer patients with poor outcome.
abstract: BACKGROUND
  The G protein-coupled oestrogen receptor, GPER, has been suggested as an alternative oestrogen receptor. Our purpose was to investigate the potential of GPER as a prognostic and predictive marker in endometrial carcinoma and to search for new drug candidates to improve treatment of aggressive disease.
  
  
  METHODS
  A total of 767 primary endometrial carcinomas derived from three patient series, including an external dataset, were studied for protein and mRNA expression levels to investigate and validate if GPER loss identifies poor prognosis and new targets for therapy in endometrial carcinoma. Gene expression levels, according to ERα/GPER status, were used to search the connectivity map database for small molecular inhibitors with potential for treatment of metastatic disease for receptor status subgroups.
  
  
  RESULTS
  Loss of GPER protein is significantly correlated with low GPER mRNA, high FIGO stage, non-endometrioid histology, high grade, aneuploidy and ERα loss (all P-values ≤0.05). Loss of GPER among ERα-positive patients identifies a subgroup with poor prognosis that until now has been unrecognised, with reduced 5-year survival from 93% to 76% (P=0.003). Additional loss of GPER from primary to metastatic lesion counterparts further supports that loss of GPER is associated with disease progression.
  
  
  CONCLUSIONS
  These results support that GPER status adds clinically relevant information to ERα status in endometrial carcinoma and suggest a potential for new inhibitors in the treatment of metastatic endometrial cancers with ERα expression and GPER loss.
authors.affiliation: Department of Clinical Medicine, Section for Gynecology and Obstetrics, University of Bergen, Jonas Lies Vei 72, Bergen 5020, Norway. camilla.krakstad@med.uib.no
authors.forename: C
authors.initials: C
authors.lastname: Krakstad
authors.forename: J
authors.initials: J
authors.lastname: Trovik
authors.forename: E
authors.initials: E
authors.lastname: Wik
authors.forename: I B
authors.initials: IB
authors.lastname: Engelsen
authors.forename: H M J
authors.initials: HM
authors.lastname: Werner
authors.forename: E
authors.initials: E
authors.lastname: Birkeland
authors.forename: M B
authors.initials: MB
authors.lastname: Raeder
authors.forename: A M
authors.initials: AM
authors.lastname: Øyan
authors.forename: I M
authors.initials: IM
authors.lastname: Stefansson
authors.forename: K H
authors.initials: KH
authors.lastname: Kalland
authors.forename: L A
authors.initials: LA
authors.lastname: Akslen
authors.forename: H B
authors.initials: HB
authors.lastname: Salvesen
mesh_terms: D000328:Adult; D000368:Aged; D016889:Endometrial Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D047628:Estrogen Receptor alpha / Q000032:analysis*; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use; D006801:Humans; D008875:Middle Aged; D011960:Receptors, Estrogen / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D016896:Treatment Outcome
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C109584:GPER1 protein, human; D056572:Histone Deacetylase Inhibitors; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled