Wnt Pathway Inhibitors Are Strongly Down-Regulated in Pituitary Tumors

• Published in: Endocrinology (Philadelphia) Vol. 149; no. 3; pp. 1235 - 1242
• Main Authors: Elston, Marianne S, Gill, Anthony J, Conaglen, John V, Clarkson, Adele, Shaw, Janet M, Law, Andrew J. J, Cook, Raymond J, Little, Nicholas S, Clifton-Bligh, Roderick J, Robinson, Bruce G, McDonald, Kerrie L
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01.03.2008
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Adult; Aged; Aged, 80 and over; Animals; beta Catenin - metabolism; Biological and medical sciences; Case-Control Studies; Cell Line; Cell Proliferation; Cyclin D1 - metabolism; Down-Regulation - physiology; Extracellular Matrix Proteins - metabolism; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Neoplastic - physiology; Glycoproteins - metabolism; Humans; Intercellular Signaling Peptides and Proteins - metabolism; Male; Membrane Proteins - metabolism; Middle Aged; Pituitary Neoplasms - etiology; Pituitary Neoplasms - metabolism; Pituitary Neoplasms - pathology; Proto-Oncogene Proteins - metabolism; Rats; Repressor Proteins - metabolism; Somatotrophs - metabolism; Transfection; Vertebrates: endocrinology; Pituitary gland; Tumor; Endocrine gland
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2007-0542

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-β-catenin pathway. Nuclear accumulation of β-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.