title: Loss of expression for the Wnt pathway components adenomatous polyposis coli and glycogen synthase kinase 3-beta in parathyroid carcinomas.
abstract: The development of parathyroid carcinoma has been associated with inactivating mutations of the Hyperparathyroidism type 2 (HRPT2) gene encoding parafibromin, a member of the human RNA Polymerase II-Associated Factor Complex (hPAF) and functionally linked to the Wingless type (Wnt) pathway. In this study, we characterized the expression of Wnt pathway molecules in parathyroid benign and malignant tumors. Tumors were investigated by immunohistochemistry supplemented with Western blot analyses using monoclonal antibodies. The study comprised 13 tumors from 12 cases of unequivocal parathyroid carcinoma, 18 cases of parathyroid adenoma, as well as non-tumorous parathyroid tissue. Adenomatous polyposis coli (APC) was uniformly expressed in non-tumorous parathyroid tissue and adenomas, but absent in carcinomas from 9 of 12 patients (75%). Expression of glycogen synthase kinase 3-beta (GSK3-beta) was lost in 4/12 carcinomas and in 1/18 adenomas. The loss of APC and GSK3-beta did not lead to augmentation of the Wnt target protein cyclin D1 or the Wnt oncoprotein beta-catenin. Active beta-catenin showed cytoplasmic and nuclear expression in all non-tumorous tissues and tumors. Loss of APC immunoreactivity was significantly associated with parathyroid carcinoma as compared to adenomas (p<0.001), giving a high specificity (100%) and sensitivity (75%) for the detection of parathyroid malignancy. The results suggest the involvement of Wnt-pathway members APC and GSK3-beta in parathyroid carcinoma development. In addition, APC immunohistochemistry could become a useful tool for improved recognition of parathyroid carcinoma together with immunohistochemistry for parafibromin and proliferation index. Furthermore, the involvement of APC related pathways in the disease development opens possibilities to explore therapeutic routes complementary to surgery.
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital Solna, SE-171 76 Stockholm, Sweden.
authors.forename: C Christofer
authors.initials: CC
authors.lastname: Juhlin
authors.forename: Felix
authors.initials: F
authors.lastname: Haglund
authors.forename: Andrea
authors.initials: A
authors.lastname: Villablanca
authors.forename: Lars
authors.initials: L
authors.lastname: Forsberg
authors.forename: Kerstin
authors.initials: K
authors.lastname: Sandelin
authors.forename: Robert
authors.initials: R
authors.lastname: Bränström
authors.forename: Catharina
authors.initials: C
authors.lastname: Larsson
authors.forename: Anders
authors.initials: A
authors.lastname: Höög
mesh_terms: D000236:Adenoma / Q000201:enzymology / Q000235:genetics; D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D000328:Adult; D000368:Aged; D002277:Carcinoma / Q000201:enzymology / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000235:genetics; D010282:Parathyroid Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D012680:Sensitivity and Specificity; D051153:Wnt Proteins / Q000235:genetics*
chemical_list: D051153:Wnt Proteins; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3