AIMS: Desmoid-type fibromatosis (DF) is a rare benign myofibroblastic neoplasm of the connective tissue that is unable to metastasize but is associated with a high local recurrence rate. Nuclear β-catenin is the most commonly used histological marker of DF; however, clinical and biological predictive markers guiding the treatment and follow-up of DF are still lacking. Normally, β-catenin is regulated by the cytoplasmic multiprotein complex of adenomatous polyposis coli (APC), axin, casein kinase 1α (CK1α), and glycogen synthase kinase 3β (GSK-3β); this phosphorylates and degrades β-catenin, which would otherwise translocate to the nucleus. The aim of this study was to analyse the expression and localization of the β-catenin-protein complex of the Wnt pathway in cells isolated from DF patients. METHODS AND RESULTS: We isolated cells from biopsies of DF patients, and demonstrated, by immunofluorescence and immunoblot analyses, that it is almost exclusively nuclear GSK-3β that colocalizes and interacts with β-catenin. The nuclear translocation of β-catenin and GSK-3β is not correlated with CTNNB1 mutations. In DF samples, the multiprotein complex is disrupted, as the cytoplasmic localization of APC and axin makes interaction with the nuclear β-catenin and GSK-3β impossible. CONCLUSIONS: Our data suggest that GSK-3β is an additional DF marker with an important role in the aetiopathogenesis of this entity.
AIMS: Desmoid-type fibromatosis (DF) is a rare benign myofibroblastic neoplasm of the connective tissue that is unable to metastasize but is associated with a high local recurrence rate. Nuclear β-catenin is the most commonly used histological marker of DF; however, clinical and biological predictive markers guiding the treatment and follow-up of DF are still lacking. Normally, β-catenin is regulated by the cytoplasmic multiprotein complex of adenomatous polyposis coli (APC), axin, casein kinase 1α (CK1α), and glycogen synthase kinase 3β (GSK-3β); this phosphorylates and degrades β-catenin, which would otherwise translocate to the nucleus. The aim of this study was to analyse the expression and localization of the β-catenin-protein complex of the Wnt pathway in cells isolated from DF patients. METHODS AND RESULTS: We isolated cells from biopsies of DF patients, and demonstrated, by immunofluorescence and immunoblot analyses, that it is almost exclusively nuclear GSK-3β that colocalizes and interacts with β-catenin. The nuclear translocation of β-catenin and GSK-3β is not correlated with CTNNB1 mutations. In DF samples, the multiprotein complex is disrupted, as the cytoplasmic localization of APC and axin makes interaction with the nuclear β-catenin and GSK-3β impossible. CONCLUSIONS: Our data suggest that GSK-3β is an additional DF marker with an important role in the aetiopathogenesis of this entity.
Authors: Shivaani Kummar; Geraldine O'Sullivan Coyne; Khanh T Do; Baris Turkbey; Paul S Meltzer; Eric Polley; Peter L Choyke; Robert Meehan; Rasa Vilimas; Yvonne Horneffer; Lamin Juwara; Ann Lih; Amul Choudhary; Sandra A Mitchell; Lee J Helman; James H Doroshow; Alice P Chen Journal: J Clin Oncol Date: 2017-03-28 Impact factor: 44.544