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E-cadherin can limit the transforming properties of activating beta-catenin mutations
Canc Res UK Beatson Inst, Glasgow, Lanark, Scotland..
Canc Res UK Beatson Inst, Glasgow, Lanark, Scotland..
Canc Res UK Beatson Inst, Glasgow, Lanark, Scotland..
ASTAR, Inst Med Biol, Singapore, Singapore..
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2015 (English)In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 34, no 18, 2321-2333 p.Article in journal (Refereed) Published
Abstract [en]

Wnt pathway deregulation is a common characteristic of many cancers. Only colorectal cancer predominantly harbours mutations in APC, whereas other cancer types (hepatocellular carcinoma, solid pseudopapillary tumours of the pancreas) have activating mutations in beta-catenin (CTNNB1). We have compared the dynamics and the potency of beta-catenin mutations in vivo. Within the murine small intestine (SI), an activating mutation of beta-catenin took much longer to achieve Wnt deregulation and acquire a crypt-progenitor cell (CPC) phenotype than Apc or Gsk3 loss. Within the colon, a single activating mutation of beta-catenin was unable to drive Wnt deregulation or induce the CPC phenotype. This ability of beta-catenin mutation to differentially transform the SI versus the colon correlated with higher expression of E-cadherin and a higher number of E-cadherin: beta-catenin complexes at the membrane. Reduction in E-cadherin synergised with an activating mutation of beta-catenin resulting in a rapid CPC phenotype within the SI and colon. Thus, there is a threshold of beta-catenin that is required to drive transformation, and E-cadherin can act as a buffer to sequester mutated beta-catenin.

Place, publisher, year, edition, pages
2015. Vol. 34, no 18, 2321-2333 p.
Keyword [en]
APC, beta-catenin, colorectal cancer, E-cadherin
National Category
Cancer and Oncology Cell and Molecular Biology
URN: urn:nbn:se:uu:diva-265922DOI: 10.15252/embj.201591739ISI: 000362457500004PubMedID: 26240067OAI: oai:DiVA.org:uu-265922DiVA: diva2:867009
EU, FP7, Seventh Framework Programme, 278568
Available from: 2015-11-04 Created: 2015-11-04 Last updated: 2015-11-04Bibliographically approved

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