title: A pan-cancer analysis of secreted Frizzled-related proteins: re-examining their proposed tumour suppressive function.
abstract: Secreted frizzled-related proteins (SFRPs), containing five family members (SFRPs 1-5) are putative extracellular Wnt inhibitors. Given their abilities to inhibit Wnt signalling, as well as the loss of SFRP1 in many cancers, this family is generally considered to be tumour suppressive. In this study we analyzed gene expression, promoter methylation and survival data from over 8000 tumour and normal samples from 29 cancers in order to map the context-specific associations of SFRPs 1-5 with patient survival, gene silencing and gene expression signatures. We show that only SFRP1 associates consistently with tumour suppressive functions, and that SFRP2 and SFRP4 typically associate with a poor prognosis concomitant with the expression of genes associated with epithelial-to-mesenchymal transition. Moreover, our results indicate that while SFRP1 is lost in cancer cells via the process of DNA methylation, SFRP2 and 4 are likely derived from the tumour stroma, and thus tend to increase in tumours as compared to normal tissues. This in-depth analysis highlights the need to study each SFRP as a separate entity and suggests that SFRP2 and SFRP4 should be approached as complex matricellular proteins with functions that extend far beyond their putative Wnt antagonistic ability.
authors.affiliation: Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, 114th St and 87th Ave, Edmonton, AB, T6G 2E1, Canada.|Department of Anatomy and Cell Biology, Faculty of Medicine and Dentistry, University of Western Ontario, 1151 Richmond St, London, ON, N6A 3K7, Canada.
authors.forename: Krista Marie
authors.initials: KM
authors.lastname: Vincent
authors.affiliation: Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, 114th St and 87th Ave, Edmonton, AB, T6G 2E1, Canada.
authors.forename: Lynne-Marie
authors.initials: LM
authors.lastname: Postovit
mesh_terms: D019175:DNA Methylation; D058750:Epithelial-Mesenchymal Transition; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics / Q000473:pathology*; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016019:Survival Analysis; D060449:Wnt Signaling Pathway; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; C117636:SFRP1 protein, human; D000094742:Secreted Frizzled-Related Proteins; C109618:SFRP2 protein, human; C118723:SFRP4 protein, human