Over the past three decades, molecular genetic studies have revealed some critical mutations underlying the pathogenesis of the sporadic and inherited forms of colorectal cancer (CRC). A relatively limited number of oncogenes and tumor-suppressor genes—most prominently the APC, KRAS, and p53 genes—are mutated in a sizeable fraction of CRCs, and a larger collection of genes that are mutated in subsets of CRC have begun to be defined. Together with DNA-methylation and chromatin-structure changes, the mutations act to dysregulate conserved signaling networks that exert context-dependent effects on critical cell phenotypes, including the regulation of cellular metabolism, proliferation, differentiation, and survival. Much work remains to be done to fully understand the nature and significance of the individual and collective genetic and epigenetic defects in CRC. Some key concepts for the field have emerged, two of which are emphasized in this review. Specifically, the gene defects in CRC often target proteins and pathways that exert pleiotropic effects on the cancer cell phenotype, and particular genetic and epigenetic alterations are linked to biologically and clinically distinct subsets of CRC.

Current models predict that β-catenin (β-cat) functions in Wnt signaling via activation of Tcf/Lef target genes and that its abundance is regulated by the adenomatous polyposis coli (APC) and glycogen synthase kinase 3β (GSK3β) proteins. In colon and other cancers, mutations in APC or presumptive GSK3β phosphorylation sites of β-cat are associated with constitutive activation of Tcf/Lef transcription. In spite of assumptions about its oncogenic potential, prior efforts to demonstrate that mutated β-cat will induce neoplastic transformation have yielded equivocal results. We report here that mutated, but not wild-type, β-cat proteins induced neoplastic transformation of RK3E, an adenovirus E1A-immortalized epithelial cell line. Analysis of the properties of mutant β-cat proteins and studies with a dominant negative Tcf-4 mutant indicated that the ability of β-cat to bind and activate Tcf/Lef factors is crucial for transformation. c-myc has recently been implicated as a critical Tcf-regulated target gene. However, c-myc was not consistently activated in β-cat-transformed RK3E cells, and a dominant negative c-Myc mutant protein failed to inhibit β-cat transformation. Our findings underscore the role of β-cat mutations and Tcf/Lef activation in cancer and illustrate a useful system for defining critical factors in β-cat transformation.

Wnts have key roles in many developmental processes, including hair follicle growth and differentiation. Stabilization of β-catenin is essential in the canonical Wnt signaling pathway. We developed transgenic mice expressing a regulated form of β-catenin in the skin. Chronic activation of β-catenin in resting (telogen) hair follicles resulted in changes consistent with induction of an exaggerated, aberrant growth phase (anagen). Transient activation of β-catenin produced a normal anagen. Our data lend strong support to the notion that a Wnt/β-catenin signal operating on hair follicle precursor cells serves as a crucial proximal signal for the telogen–anagen transition.