title: Loss of secreted frizzled-related protein 4 correlates with an aggressive phenotype and predicts poor outcome in ovarian cancer patients.
abstract: BACKGROUND
  Activation of the Wnt signaling pathway is implicated in aberrant cellular proliferation in various cancers. In 40% of endometrioid ovarian cancers, constitutive activation of the pathway is due to oncogenic mutations in β-catenin or other inactivating mutations in key negative regulators. Secreted frizzled-related protein 4 (SFRP4) has been proposed to have inhibitory activity through binding and sequestering Wnt ligands.
  
  
  RESULTS
  We performed RT-qPCR and Western-blotting in primary cultures and ovarian cell lines for SFRP4 and its key downstream regulators activated β-catenin, β-catenin and GSK3β. SFRP4 was then examined by immunohistochemistry in a cohort of 721 patients and due to its proposed secretory function, in plasma, presenting the first ELISA for SFRP4. SFRP4 was most highly expressed in tubal epithelium and decreased with malignant transformation, both on RNA and on protein level, where it was even more profound in the membrane fraction (p<0.0001). SFRP4 was expressed on the protein level in all histotypes of ovarian cancer but was decreased from borderline tumors to cancers and with loss of cellular differentiation. Loss of membrane expression was an independent predictor of poor survival in ovarian cancer patients (p = 0.02 unadjusted; p = 0.089 adjusted), which increased the risk of a patient to die from this disease by the factor 1.8.
  
  
  CONCLUSIONS
  Our results support a role for SFRP4 as a tumor suppressor gene in ovarian cancers via inhibition of the Wnt signaling pathway. This has not only predictive implications but could also facilitate a therapeutic role using epigenetic targets.
authors.affiliation: Translational Research Group, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Francis
authors.initials: F
authors.lastname: Jacob
authors.forename: Kristjan
authors.initials: K
authors.lastname: Ukegjini
authors.forename: Sheri
authors.initials: S
authors.lastname: Nixdorf
authors.forename: Caroline E
authors.initials: CE
authors.lastname: Ford
authors.forename: Jake
authors.initials: J
authors.lastname: Olivier
authors.forename: Rosmarie
authors.initials: R
authors.lastname: Caduff
authors.forename: James P
authors.initials: JP
authors.lastname: Scurry
authors.forename: Rea
authors.initials: R
authors.lastname: Guertler
authors.forename: Daniela
authors.initials: D
authors.lastname: Hornung
authors.forename: Renato
authors.initials: R
authors.lastname: Mueller
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Fink
authors.forename: Neville F
authors.initials: NF
authors.lastname: Hacker
authors.forename: Viola A
authors.initials: VA
authors.lastname: Heinzelmann-Schwarz
mesh_terms: D001201:Ascites / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D015331:Cohort Studies; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D009361:Neoplasm Invasiveness; D010051:Ovarian Neoplasms / Q000097:blood / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010641:Phenotype; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D016019:Survival Analysis; D016896:Treatment Outcome; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D011518:Proto-Oncogene Proteins; C118723:SFRP4 protein, human; D000094742:Secreted Frizzled-Related Proteins