title: Multiple signaling pathways converge on beta-catenin in thyroid cancer.
abstract: The beta-catenin pathway has been conclusively demonstrated to regulate differentiation and patterning in multiple model systems. In thyroid cancer, alterations are often seen in proteins that regulate beta-catenin, including those of the RAS, PI3K/AKT, and peroxisome proliferation activated receptor-gamma (PPARgamma) pathways, and evidence from the literature suggests that beta-catenin may play a direct role in the dedifferentiation commonly observed in late-stage disease. RET/PTC rearrangements are frequent in thyroid cancer and appear to be exclusive from mutational events in RAS and BRAF. Activation of AKT by phosphatidylinositide-3 kinase (PI3K), a RAS effector, results in GSK3beta phosphorylation and deactivation and subsequent beta-catenin upregulation in thyroid cancer. Activating mutations in beta-catenin, which have been demonstrated in late-stage thyroid tumors, correlate with beta-catenin nuclear localization and poor prognosis. We hypothesize that activation of the RAS, PI3K/AKT, and PPARgamma pathways ultimately impinges upon beta-catenin. We further propose that if mutations in BRAF, RAS, and RET/PTC rearrangements are mutually exclusive in certain thyroid tumors or tumor types, as has already been shown for papillary thyroid cancer, then these interconnected pathways may cooperate in the initiation and promotion of the disease. We believe that clinical benefit for thyroid cancer patients could be derived from disrupting the middle or distal pathway effectors of these pathways, such as AKT or beta-catenin.
authors: Indiana University School of Medicine, Medical Sciences, Bloomington, Indiana, USA. pabbosh@indiana.edu
authors: Phillip H
authors: PH
authors: Abbosh
authors: Kenneth P
authors: KP
authors: Nephew
mesh_terms: D015316:Genetic Therapy; D006801:Humans; D015398:Signal Transduction; D013964:Thyroid Neoplasms / Q000378:metabolism* / Q000473:pathology*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051176:beta Catenin