The WNT signaling pathway has been linked with cancer ever since the identification of the first WNT as a gene activated by integration of mouse mammary tumor virus proviral DNA in virally-induced breast tumors (Nusse et al, 1984). The most well known example of aberrant WNT signaling in cancer is in colorectal cancer, where an activating mutation in a WNT pathway component is seen in 90% of sporadic cases. Inappropriate WNT pathway activation has also been implicated in most other solid human cancers but is not always associated with mutations in WNT pathway components (reviewed in Polakis, 2012).
Both tumor suppressors and oncogenes have been identified in the so-called canonical WNT pathway, which regulates WNT-dependent transcription by promoting the degradation of beta-catenin in the absence of ligand (reviewed in Polakis, 2012). Loss-of-function mutations in the destruction complex components APC, Axin and AMER1 and gain-of-function mutations in beta-catenin itself cause constitutive signaling and are found in cancers of the intestine, kidney, liver and stomach, among others (Polakis, 1995; Segiditsas and Tomlinson, 2006; Peifer and Polakis, 2000; Laurent-Puig et al, 2001; Liu et al, 2000; Satoh et al, 2000; Major et al, 2007; Ruteshouser et al, 2008). WNTs and WNT pathway components are also frequently over- or under-expressed in various cancers, and these changes are correlated with epigenetic regulation of promoter activity. In some contexts, both the canonical and non-canonical WNT signaling, which governs processes such as cell polarity and morphogenesis, may also contribute to tumor formation by promoting cell migration, invasiveness and metastasis.