Multiple signaling pathways converge on β-catenin in thyroid cancer

Phillip H. Abbosh, Kenneth P. Nephew

Research output: Contribution to journalReview article

42 Scopus citations


The β-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 β-catenin, including those of the RAS, PI3K/AKT, and peroxisome proliferation activated receptor-γ (PPARγ) pathways, and evidence from the literature suggests that β-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 GSK3β phosphorylation and deactivation and subsequent β-catenin upregulation in thyroid cancer. Activating mutations in β-catenin, which have been demonstrated in late-stage thyroid tumors, correlate with β-catenin nuclear localization and poor prognosis. We hypothesize that activation of the RAS, PI3K/AKT, and PPARγ pathways ultimately impinges upon β-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 β-catenin.

Original languageEnglish (US)
Pages (from-to)551-561
Number of pages11
Issue number6
StatePublished - Jun 1 2005

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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