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β-Catenin signaling dosage dictates tissue-specific tumor predisposition in Apc-driven cancer

Oncogene volume 32, pages 4579–4585 (2013)Cite this article

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Abstract

Apc-driven tumor formation in patients and Apc-mutant mouse models is generally attributed to increased levels of β-catenin signaling. We and others have proposed that a specific level of β-catenin signaling is required to successfully initiate tumor formation, and that each tissue prefers different dosages of signaling. This is illustrated by APC genotype−tumor phenotype correlations in cancer patients, and by the different tumor phenotypes displayed by different Apc-mutant mouse models. Apc1638N mice, associated with intermediate β-catenin signaling, characteristically develop intestinal tumors (<10) and extra-intestinal tumors, including cysts and desmoids. Apc1572T mice associated with lower levels of β-catenin signaling are free of intestinal tumors, but instead develop mammary tumors. Although the concept of β-catenin signaling dosage and its impact on tumor growth among tissues is gaining acceptance, it has not been formally proven. Additionally, alternative explanations for Apc-driven tumor formation have been proposed. To obtain direct evidence for the dominant role of β-catenin dosage in tumor formation and tissue-specific tumor predisposition, we crossed Apc1638N mice with heterozygous β-catenin knockout mice, thereby reducing β-catenin levels. Whereas all the Apc1638N;Ctnnb1+/+ mice developed gastrointestinal tumors, none were present in the Apc1638N;Ctnnb1−/+ mice. Incidence of other Apc1638N-associated lesions, including desmoids and cysts, was strongly reduced as well. Interestingly, Apc1638N;Ctnnb1−/+ females showed an increased incidence of mammary tumors, which are normally rarely observed in Apc1638N mice, and the histological composition of the tumors resembled that of Apc1572T-related tumors. Hereby, we provide in vivo genetic evidence confirming the dominant role of β-catenin dosage in tumor formation and in dictating tumor predisposition among tissues in Apc-driven cancer.

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Acknowledgements

We thank Dr J Huelsken for providing Ctnnb1fl/+ mice.

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Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands

    E R M Bakker, E Hoekstra, W Helvensteijn, W van Veelen, E J Kuipers & R Smits

  2. Department of Pathology, Erasmus MC University Medical Center, Rotterdam, The Netherlands

    P F Franken & C H M van Deurzen

  3. Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands

    E J Kuipers

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  1. E R M Bakker
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Correspondence to R Smits.

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Bakker, E., Hoekstra, E., Franken, P. et al. β-Catenin signaling dosage dictates tissue-specific tumor predisposition in Apc-driven cancer. Oncogene 32, 4579–4585 (2013). https://doi.org/10.1038/onc.2012.449

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  • DOI: https://doi.org/10.1038/onc.2012.449

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