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Friday 11 July 2003

CTNNB1, cadherin-associated protein, beta-catenin


Definition: Protein encoded by CTNNB1 gene, coordinates cell–cell adhesion and gene transcription.


- Part of Wnt signalling pathway, highly conserved pathway with critical role in embryologic development (Dev Cell 2009;17:9), carcinogenesis and epithelial-to-mesenchymal transition.

- Upon Wnt activation, β-catenin is translocated from membrane (where it interacts with E-cadherin) to cytoplasm and nucleus, where it interacts with transcriptional activators

- Beta-catenin is an adherens junction protein. Beta-Catenin is a multifunctional protein related to the adherens junction and to signal transduction.

- Beta-catenin is a key molecule of cell proliferation. Its role is central to epithelial architecture, regulating the polarity of cells and tissues.

- Beta-catenin (CTNNB1) (MIM.116806) and plakoglobin are substrates for tyrosine phosphorylation following EGF stimulation of cells.


- cadherin-catenin complex
- beta-catenin/APC pathway

Targets - Ligands

- Wnt


- somatic mutations in tumors

- promoter swapping

- Mutations and overexpression of β-catenin are associated with various carcinomas
Colon: plays a critical role in tumorigenesis (mutations in APC or β-catenin present in 90% of colon cancers)
- Thyroid: pathway important for anaplastic and possibly papillary thyroid carciomas (Front Endocrinol (Lausanne) 2012;3:31)
- Uterus: endometrioid endometrial carcinoma is associated with β-catenin mutations

Diagnostic immunochemistry

- Nuclear staining is significant in fibroblasts;
- nuclear or cytoplasmic staining is significant in epithelial cells

- hepatocellular adenoma

  • Classify hepatocellular adenoma subtypes and distinguish from focal nodular hyperplasia (Am J Surg Pathol 2012;36:1691, Int J Hepatol 2013;2013:268625, Hum Pathol 2013;44:750)

- desmoid fibromatosis

  • IHC positive with nuclear positivity
  • mutated in fibromatosis (Mod Pathol 2012;25:1551)
  • Distinguish mesenteric fibromatosis (positive with nuclear staining due to mutations in APC / β-catenin pathway causing nuclear accumulation) from GIST tumors (negative) and sclerosing mesenteritis (negative, Am J Surg Pathol 2002;26:1296)

- desmoid fibromatosis vs low-grade fibromyxoid sarcoma differential diagnosis

  • beta-catenin expression in desmoid fibromatosis / negative in low-grade fibromyxoid sarcoma
  • Distinguish fibromatosis (diffuse or rarely focal nuclear staining for deep tumors) from low grade fibromyxoid sarcoma and other myofibroblastic, or fibroblastic tumors / sarcomas (negative for nuclear staining, Am J Surg Pathol 2005;29:653)

- neuroblastoma

  • Identify isolated tumor cells in neuroblastoma (Am J Clin Pathol 2009;131:49)

- nasopharyngeal carcinoma

  • Poor prognostic factor for nasopharyngeal carcinoma (Hum Pathol 2013;44:1357)

- renal cell carcinoma (RCC)

  • Cytoplasmic expression of ß-catenin is an independent predictor of progression of conventional renal cell carcinoma: a simple immunostaining score (doi : 10.1111/his 13059)


- Mizumoto K, Sawa H. Two betas or not two betas: regulation of asymmetric division by beta-catenin. Trends Cell Biol. 2007 Oct;17(10):465-73. Epub 2007 Oct 4. Review. PMID: 17919911

- Nathke I. Cytoskeleton out of the cupboard: colon cancer and cytoskeletal changes induced by loss of APC. Nat Rev Cancer. 2006 Dec;6(12):967-74. PMID: 17093505

- Lilien J, Balsamo J. The regulation of cadherin-mediated adhesion by tyrosine phosphorylation/dephosphorylation of beta-catenin. Curr Opin Cell Biol. 2005 Oct;17(5):459-65. PMID: 16099633

- Brembeck FH, Rosario M, Birchmeier W. Balancing cell adhesion and Wnt signaling, the key role of beta-catenin. Curr Opin Genet Dev. 2006 Feb;16(1):51-9. PMID: 16377174

- Harris TJ, Peifer M. Decisions, decisions: beta-catenin chooses between adhesion and transcription. Trends Cell Biol. 2005 May;15(5):234-7. PMID: 15866026

- Bhattacharya B, Dilworth HP, Iacobuzio-Donahue C, Ricci F, Weber K, Furlong MA, Fisher C, Montgomery E. Nuclear beta-Catenin Expression Distinguishes Deep Fibromatosis From Other Benign and Malignant Fibroblastic and Myofibroblastic Lesions. Am J Surg Pathol. 2005 May;29(5):653-659. PMID: 15832090

- Bienz M. beta-Catenin: A Pivot between Cell Adhesion and Wnt Signalling. Curr Biol. 2005 Jan 26;15(2):R64-7. PMID: 15668160

- Moon RT, Kohn AD, Ferrari GV, Kaykas A. WNT and beta-catenin signalling: diseases and therapies. Nat Rev Genet. 2004 Sep;5(9):691-701. PMID: 15372092


- β-Catenin (CTNNB1) mutations and clinicopathological features of mesenteric desmoid-type fibromatosis. Huss S, Nehles J, Binot E, Wardelmann E, Mittler J, Kleine MA, Künstlinger H, Hartmann W, Hohenberger P, Merkelbach-Bruse S, Buettner R, Schildhaus HU. Histopathology. 2013 Jan;62(2):294-304. doi : 10.1111/j.1365-2559.2012.04355.x PMID: 23020601

- Amary MF, Pauwels P, Meulemans E, Roemen GM, Islam L, Idowu B, Bousdras K, Diss TC, O’Donnell P, Flanagan AM. Detection of beta-catenin mutations in paraffin-embedded sporadic desmoid-type fibromatosis by mutation-specific restriction enzyme digestion (MSRED): an ancillary diagnostic tool. Am J Surg Pathol. 2007 Sep;31(9):1299-309. PMID: 17721184