Analysis of β-catenin activation in mouse skin carcinogenesis

Abstract

β-catenin overexpression was investigated in transgenic mouse skin carcinogenesis to determine at which stage β-catenin deregulation became causal in co-operation with ras and fos oncogene activation and/or loss of tumour suppresser genes p53, p21 and PTEN. β-catenin has two major functions in being a major node for canonical Wnt signalling, nuclear relocation regulates transcriptional targets LEF/TCF and increased nuclear β-catenin expression associates with tumour progression; whilst membranous β-catenin binds to E-cadherin to form cell-cell adhesion complexes and their failure is associated with invasion. Thus, in cutaneous squamous cell carcinoma [SCC], β-catenin mutations result in constitutive overexpression via mutations in exon 3, the site for removal via ubiquination, or failures in genes that regulate β-catenin, such as APC and GSK3β. However, despite the clear relevance of β-catenin in SCC, few studies have directly explored constitutive β-catenin overexpression employing classic multi-stage mouse skin carcinogenesis to help unravel the mechanism of β-catenin deregulation. Therefore, to investigate stage-specific roles in skin carcinogenesis, β-catenin overexpression was targeted to transgenic mouse epidermis employing RU486-inducible cre/lox and expression of an exon 3-ablated β-catenin transgene [K14creP.Δ3β-cat]. The effect of β-catenin overexpression was assessed in co-operation with activated Ras [HK1.ras] and Fos [HK1.fos] and loss of PTEN-regulated AKT activation [Δ5PTEN], together with p53 and p21 ablation.