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© 2015 Cancer Research UK Beatson Institute. Published under the terms of the CC BY 4.0 license. 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 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 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 higher expression of E-cadherin and a higher number of E-cadherin:β-catenin complexes at the membrane. Reduction in E-cadherin synergised with an activating mutation of β-catenin resulting in a rapid CPC phenotype within the SI and colon. Thus, there is a threshold of β-catenin that is required to drive transformation, and E-cadherin can act as a buffer to sequester mutated β-catenin. Synopsis In contrast to other Wnt-driven malignancies colorectal cancer is usually linked to APC loss, and very rarely to β-catenin activating mutations. Different E-cadherin levels can explain the variation in transforming potential of β-catenin mutations in different tumors. Activating β-catenin mutations in the mouse small intestine but not the colon lead to Wnt-activation. Increased E-cadherin levels can buffer mutated β-catenin in the colon epithelium. β-catenin activating mutations are linked to human cancers that show reduced levels of E-cadherin. In contrast to other Wnt-driven malignancies colorectal cancer is usually linked to APC loss, and very rarely to β-catenin activating mutations. Different E-cadherin levels can explain the variation in transforming potential of β-catenin mutations in different tumors.

Original publication

DOI

10.15252/embj.201591739

Type

Journal article

Journal

EMBO Journal

Publication Date

01/01/2015

Volume

34

Pages

2321 - 2333