Inactivation of the APC tumour suppressor gene represents the rate-limiting event in colorectal cancer. Loss of APC function leads to constitutive activation of the canonical Wnt-beta-catenin signalling pathway, thus resulting into a broad spectrum of cellular defects, ranging from stem cell self-renewal and differentiation, apoptosis, migration and proliferation. Recently, Phelps et al presented an alternative model where loss of APC does not primarily result in Wnt signalling activation but rather involves the transcriptional co-repressor CtBP1. According to this alternative scenario, oncogenic KRAS activation represents a conditio sine qua non for nuclear beta-catenin translocation and Wnt activation. In a recent issue of the Journal of Pathology, Obrador-Hevia and collaborators reaffirmed the broadly accepted textbook model by showing the presence of nuclear beta-catenin in both the presence and, more often, the absence of KRAS mutations.
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