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E-cadherin can limit the transforming properties of activating β‐catenin mutations

Huels, David J., Ridgway, Rachel A., Radulescu, Sorina, Leushacke, Marc, Campbell, Andrew D., Biswas, Sujata, Leedham, Simon, Serra, Stefano, Chetty, Runjan, Moreaux, Guenievre, Parry, Lee, Matthews, James, Song, Fei, Hedley, Ann, Kalna, Gabriela, Ceteci, Fatih, Reed, Karen R., Meniel, Valerie S., Maguire, Aoife, Doyle, Brendan, Soderberg, Ola, Barker, Nick, Watson, Alastair, Larue, Lionel, Clarke, Alan R. and Sansom, Owen J. 2015. E-cadherin can limit the transforming properties of activating β‐catenin mutations. EMBO Journal 34 (18) , pp. 2321-2333. 10.15252/embj.201591739

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Abstract

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 b-catenin (CTNNB1). We have compared the dynamics and the potency of b-catenin mutations in vivo. Within the murine small intestine (SI), an activating mutation of b-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 b-catenin was unable to drive Wnt deregulation or induce the CPC phenotype. This ability of b-catenin mutation to differentially transform the SI versus the colon correlated with higher expression of E-cadherin and a higher number of E-cadherin: b-catenin complexes at the membrane. Reduction in E-cadherin synergised with an activating mutation of b-catenin resulting in a rapid CPC phenotype within the SI and colon. Thus, there is a threshold of b-catenin that is required to drive transformation, and E-cadherin can act as a buffer to sequester mutated b-catenin.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
European Cancer Stem Cell Research Institute (ECSCRI)
Publisher: EMBO Press
ISSN: 0261-4189
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 1 July 2015
Last Modified: 18 Feb 2020 18:00
URI: http://orca-mwe.cf.ac.uk/id/eprint/75607

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