Milea Timbergen

25 catenin signalling pathway, and its stability is normally regulated by a degradation complex consisting of the tumour suppressor APC, a scaffolding protein axin, and two constitutively active serine-threonine kinases i.e., casein kinase 1α (CK1α/δ), and glycogen synthase kinase 3 (GSK3). Within this complex β-catenin is sequentially phosphorylated by CK1 and GSK3 on serine/threonine residues (Ser45, Thr41, Ser37, Ser33), thus forming a docking site for the E3 ubiquitin ligase; β-TrCP. This ubiquitinylates β-catenin, which is subsequently degraded by the proteasome. Activation of the Wnt/β-catenin pathway by binding of the Wnt ligand to the frizzled/LRP heterodimer recruits the degradation complex to the membrane via the dishevelled protein (DVL) disrupting the degradation complex and consequently the phosphorylation of β-catenin, leading to its stabilization and translocation into the nucleus. In the nucleus it operates as a transcriptional activator, bound to members of the T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factor family, and possibly to other co-activators of Wnt target genes (reviewed by Nusse and Clevers 32 ). The Wnt/β-catenin signalling pathway in cancer The Wnt/β-catenin signalling pathway contributes to cancer by promoting progression of cells through the cell cycle, by inhibiting apoptosis via the expression of anti-apoptotic genes, by affecting cell proliferation via the expression of growth factors and their corresponding receptors, by influencing cell motility through the expression of cell adhesion and extracellular matrix proteins and via stem cell maintenance (reviewed by Nusse and Clevers 32 ). Aberrant signalling of the Wnt/ß-catenin pathway has been implicated in several epithelial tumours (e.g., colorectal carcinoma 34 and endometrial carcinoma 35 ) and in mesenchymal tumours (e.g., osteosarcomas 36, 37 , malignant fibrous histiocytomas and liposarcomas 38 ). The Wnt/ß-catenin signalling pathway in desmoid-type fibromatosis The relationship between the Wnt/β-catenin signalling pathway and DTF has been extensively studied. It is believed that this pathway is crucial to DTF pathogenesis because of the fact that the vast majority (about 85%) of DTF tumours harbour a mutation in exon 3 of the CTNNB1 (ß-catenin) gene, making the protein more resistant to proteolytic degradation 39-41 . Less frequently, loss-of-function mutations in the APC tumour suppressor gene are observed, most commonly in the context of FAP 12 . In both cases, β-catenin translocates into the nucleus aberrantly activating target genes. This nuclear accumulation can be determined by immunohistochemistry (IHC), and serves as a diagnostic tool differentiating DTF from other bone-, soft tissue and fibrous tumours 42 . The group of wild-type (WT) ß-catenin DTF, comprises about 15% of all DTF tumours, and is defined as “having no CTNNB1 mutations 2