title: Wnt pathway inhibitors are strongly down-regulated in pituitary tumors.
abstract: The etiology of sporadic pituitary tumors is currently unknown. The Wnt pathways have been implicated in the pathogenesis of a variety of human tumors, but the role of these pathways in pituitary tumors is unclear. Microarray analysis using the Affymetrix HG U133 plus 2.0 GeneChips identified four secreted frizzled-related protein (sFRP) family members of Wnt pathway inhibitors that were differentially expressed in both nonfunctioning and clinically functioning pituitary tumors (n = 20) compared with normal pituitary controls (n = 3). Reduced tumor expression of Wnt inhibitory factor-1 (WIF1), sFRP2, and sFRP4 mRNA was confirmed by real-time quantitative RT-PCR (P <0.001 and P = 0.002 and 0.013, respectively) in all pituitary subtypes. Hypermethylation of the WIF1 promoter was present in 88% of the pituitary tumors (n = 41). Seventy-six percent of pituitary tumors demonstrated absent or weak cytoplasmic WIF1 staining by immunohistochemistry (n = 41), although preserved staining was seen in some functioning tumors, with strong staining in 92% of normal pituitary controls (n = 13). The Wnt pathway target gene cyclin D1 was found to be up-regulated specifically in the nonfunctioning pituitary tumors compared with controls at both mRNA and protein level, supportive of activation of the Wnt-beta-catenin pathway. Nuclear accumulation of beta-catenin, however, was not observed in any pituitary tumors (n = 70). By transfecting GH3 cells with WIF1, decreased cell proliferation and colony formation was observed compared with empty vector controls. In conclusion, our data suggest that WIF1 may be a tumor suppressor, specifically in nonfunctioning pituitary tumors, and that the Wnt pathways are important in pituitary tumorigenesis.
authors: Cancer Genetics Unit, Kolling Institute of Medical Research, Royal North Shore Hospital, St. Leonards, New South Wales 2065, Australia. marianne@med.usyd.edu.au
authors: Marianne S
authors: MS
authors: Elston
authors: Anthony J
authors: AJ
authors: Gill
authors: John V
authors: JV
authors: Conaglen
authors: Adele
authors: A
authors: Clarkson
authors: Janet M
authors: JM
authors: Shaw
authors: Andrew J J
authors: AJ
authors: Law
authors: Raymond J
authors: RJ
authors: Cook
authors: Nicholas S
authors: NS
authors: Little
authors: Roderick J
authors: RJ
authors: Clifton-Bligh
authors: Bruce G
authors: BG
authors: Robinson
authors: Kerrie L
authors: KL
authors: McDonald
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D016022:Case-Control Studies; D002460:Cell Line; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology*; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D010911:Pituitary Neoplasms / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051381:Rats; D012097:Repressor Proteins / Q000378:metabolism*; D052683:Somatotrophs / Q000378:metabolism; D014162:Transfection; D051176:beta Catenin / Q000378:metabolism; D000099274:Frizzled-Related Proteins; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019938:Cyclin D1; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D051176:beta Catenin; D000099274:Frizzled-Related Proteins; C109618:SFRP2 protein, human; D000094742:Secreted Frizzled-Related Proteins; C118723:SFRP4 protein, human; C485569:WIF1 protein, human; C521045:Wif1 protein, rat