β-Catenin signaling dosage dictates tissue-specific tumor predisposition in Apc-driven cancer
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.
|Keywords||APC, intestinal cancer, mammary tumor, β-catenin|
|Persistent URL||dx.doi.org/10.1038/onc.2012.449, hdl.handle.net/1765/41608|
|Journal||Oncogene: including Oncogene Reviews|
Bakker, E.R.M, Hoekstra, E, Franken, P.F, Helvensteijn, W, van Deurzen, C.H.M, van Veelen, W, … Smits, M.J.M. (2013). β-Catenin signaling dosage dictates tissue-specific tumor predisposition in Apc-driven cancer. Oncogene: including Oncogene Reviews, 32(38), 4579–4585. doi:10.1038/onc.2012.449