E-cadherin can limit the transforming properties of activating beta-catenin mutations
2015 (English)In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 34, no 18, 2321-2333 p.Article in journal (Refereed) Published
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.
APC, beta-catenin, colorectal cancer, E-cadherin
Cancer and Oncology Cell and Molecular Biology
IdentifiersURN: urn:nbn:se:uu:diva-265922DOI: 10.15252/embj.201591739ISI: 000362457500004PubMedID: 26240067OAI: oai:DiVA.org:uu-265922DiVA: diva2:867009
FunderEU, FP7, Seventh Framework Programme, 278568