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

David Huels, Rachel Ridgeway, Sorina Radulescu, Marc Leushacke, Andrew Campbell, Sujata Biswas, Simon Leedham, Stefano Serra, Runjan Chetty, Guenieve Moreaux, Lee Parry, James Matthews, Fei Song, Ann Hedley, Gabriela Kalna, Fatih Ceteci, Karen R Reed, Valerie S Meniel, Aoife Maguire, Ola SoderbergNicholas Barker, Alastair Watson, Lionel Larue, Owen Sansom

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Abstract

Wnt pathway deregulation is a common characteristic of many cancers. But only Colorectal Cancer predominantly harbours mutations in APC, whereas other cancer types (hepatocellular carcinoma, solid pseudopapillary tumours of pancreas) have activating mutations in β-catenin (CTNNB1). We have compared the dynamics and the potency of β-catenin mutations in vivo. Within the murine small intestine (SI), an activating mutation of β-catenin took much longer to achieve a Wnt deregulation and acquire a crypt-progenitor-cell (CPC) phenotype than Apc or Gsk3 loss. Within the colon, a single activating mutation of β-catenin was unable to drive Wnt deregulation or induce the CPC phenotype. This ability of β-catenin mutation to differentially transform the SI versus the colon correlated with significantly higher expression of the β-catenin binding partner E-cadherin. This increased expression is associated with a higher number of E-cadherin:β-catenin complexes at the membrane. Reduction of E-cadherin synergised with an activating mutation of β-catenin so there was now a rapid CPC phenotype within the colon and SI. Thus there is a threshold of β-catenin that is required to drive transformation and E-cadherin can act as a buffer to prevent β-catenin accumulation.
Original languageEnglish
Pages (from-to)2321-2333
Number of pages13
JournalThe EMBO Journal
Volume34
Issue number18
Early online date3 Aug 2015
DOIs
Publication statusPublished - 14 Sep 2015

Keywords

  • APC
  • B-catenin
  • Colorectal Cancer
  • E-cadherin

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