Beta-catenin: a transforming actor on many stages

Abstract

Mutations and deletions that result in the stabilization of beta-catenin are frequently found in a number of tumors, including those of the colon, the liver and the ovary, but are less frequently found in breast cancer. To investigate and understand the molecular nature of cell-specific beta-catenin signaling, experimental mouse genetics has been employed extensively. Gain-of-function and loss-of-function mutations have provided evidence that beta-catenin plays essential roles in development and tumorigenesis. Specifically, the Wnt/beta-catenin signaling pathway controls cell fate decisions throughout development, and a unique role in differentiated epithelia has emerged. Not only beta-catenin, but also the activation of other components of this pathway in differentiated mammary epithelium and prostate epithelium of transgenic mice can induce neoplasias and transdifferentiation to squamous metaplasias. This suggests that the Wnt/beta-catenin pathway is dominant over existing differentiation programs and can impose an epidermal fate or neoplasias onto a variety of cell types. Although there is evidence for a contextual specificity of the Wnt signaling, the experimental systems and designs used in different studies probably influence the cellular responses.

Figure 1

Activated β-catenin altered the fate of epithelial cells. In skin, activated β-catenin induced hair follicles and tumors. In mammary epithelia, activated β-catenin could induce adenocarcinomas (MMTV-ΔN89), squamous metaplasias (WAP/MMTV-ΔExon3) or both (MMTV-ΔN90). MMTV, mouse mammary tumor virus; WAP, whey acidic protein.

Figure 2

Canonic Wnt signaling pathway molecules can induce a similar phenotype. When each molecule in the canonic Wnt signaling pathway was activated, they could induce hyperplasias, adenocarcinomas and squamous metaplasias. GSK3, dominant negative glycogen synthase kinase 3β; APC, adenomatous polyposis coli; P, phosphorylated form; dsh, dishevelled.