title: Loss of progesterone receptor links to high proliferation and increases from primary to metastatic endometrial cancer lesions.
abstract: OBJECTIVE
  In endometrial cancer loss of progesterone receptor (PR, gene name PGR) is associated with aggressive disease and altered response to hormonal treatment. The aim of this study was to investigate changes in PR expression level with disease progression, and explore whether differences in gene expression according to PR status can be linked to processes involved in cancer development elucidating new therapeutic opportunities.
  
  
  METHODS
  686 primary endometrial cancers and 171 metastatic lesions were investigated for PR expression in relation to clinical and histopathological data. Protein levels were investigated by immunohistochemistry and reverse phase protein array, and mRNA levels by DNA oligonucleotide microarray.
  
  
  RESULTS
  PR protein level was significantly associated with PGR mRNA expression (P<0.001) and patient survival (P<0.001). Loss of PR increased with disease progression, with 23% of the primary tumours and 76% of metastases demonstrating PR loss. Using a cell cycle progression signature score, PR loss was associated with increased proliferation for both oestrogen receptor (ER) positive and negative tumours. Through a Connectivity Map search, CDK inhibitors and other drugs with anti-proliferative effects were suggested in particular for treatment of patients with loss of PR.
  
  
  CONCLUSIONS
  Loss of PR in endometrial cancer is associated with increased proliferation, poor survival, and increases from primary to metastatic lesions. Based on expression profiles, CDK inhibitors may have activity in PR negative tumours, supporting further testing in clinical trials for patients with systemic endometrial cancer dependent on PR status.
authors.affiliation: Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Norway; Department of Gynecology and Obstetrics, Haukeland University Hospital, Norway.
authors.forename: Ingvild Løberg
authors.initials: IL
authors.lastname: Tangen
authors.affiliation: Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Norway; Department of Gynecology and Obstetrics, Haukeland University Hospital, Norway.
authors.forename: Henrica M J
authors.initials: HM
authors.lastname: Werner
authors.affiliation: Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Norway; Department of Gynecology and Obstetrics, Haukeland University Hospital, Norway.
authors.forename: Anna
authors.initials: A
authors.lastname: Berg
authors.affiliation: Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Norway; Department of Gynecology and Obstetrics, Haukeland University Hospital, Norway.
authors.forename: Mari K
authors.initials: MK
authors.lastname: Halle
authors.affiliation: Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Norway; Department of Gynecology and Obstetrics, Haukeland University Hospital, Norway; Computational Biology Unit, University of Bergen, Bergen, Norway.
authors.forename: Kanthida
authors.initials: K
authors.lastname: Kusonmano
authors.affiliation: Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Norway; Department of Gynecology and Obstetrics, Haukeland University Hospital, Norway.
authors.forename: Jone
authors.initials: J
authors.lastname: Trovik
authors.affiliation: Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Norway; Department of Gynecology and Obstetrics, Haukeland University Hospital, Norway.
authors.forename: Erling A
authors.initials: EA
authors.lastname: Hoivik
authors.affiliation: Department of Systems Biology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Norway; Department of Gynecology and Obstetrics, Haukeland University Hospital, Norway.
authors.forename: Camilla
authors.initials: C
authors.lastname: Krakstad
authors.affiliation: Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Norway; Department of Gynecology and Obstetrics, Haukeland University Hospital, Norway.
authors.forename: Helga B
authors.initials: HB
authors.lastname: Salvesen
mesh_terms: D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D002867:Chromones / Q000627:therapeutic use; D018450:Disease Progression; D016889:Endometrial Neoplasms / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D009025:Morpholines / Q000627:therapeutic use; D020411:Oligonucleotide Array Sequence Analysis; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020123:Sirolimus / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: D000903:Antibiotics, Antineoplastic; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D011980:Receptors, Progesterone; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: CDK inhibitors; Endometrial cancer; Progesterone receptor; Survival