P23 Inducible E-cadherin ablation drives malignant progression in HK1.ras.fos.PTENflx/flx carcinogenesis and induces conversion of HK1.fos.PTENflx/flx keratoacanthoma

Abstract Inducible ablation of E-cadherin expression has been investigated in mouse skin carcinogenesis driven by Ras and Fos activation (HK1.ras; HK1.fos), and conditional (cre/lox) PTEN knockout exclusively in the epidermis. Previously, analysis of endogenous E-cadherin expression in stage-specific HK1.ras/fos/Δ5PTEN tumours showed E-cadherin expression became reduced at the invasive front of well-differentiated squamous cell carcinomas (wdSCCs) following p53 loss, and where retention of p21 minimized Akt activation and further progression. To validate stage-specific causality of E-cadherin loss, RU486-inducible conditional E-cadherin knockout was introduced into HK1.ras/fos/Δ5PTENflx/flx genotypes employing the cre/LoxP system (K14cre-ΔE-cadflx/flx). Initial observations in RU486-treated compound HK1.ras/fos/ΔPTENflx/flx-ΔE-cadflx/flx mice found that E-cadherin ablation appeared to accelerate malignant conversion, again associated with p53 loss; however, the main effect was on malignant progression and invasion, as wdSCCs displayed rapid progression to aggressive SCCs. Malignant progression also implicated β-catenin activation, finding increased nuclear expression, alongside loss of membranous expression, in the invasive basal layer keratinocytes, together with loss of p21 and increased p-Akt1 activity. In addition, preliminary data for E-cadherin loss in HK1.fos/Δ5PTEN keratoacanthoma aetiology now showed malignant conversion to invasive wdSCC, again associated with increased β-catenin activation. These wdSCCs may have retained a degree of correct adhesion signalling, as basal layer HK1.fos/Δ5PTEN-ΔE-cadflx/flx keratinocytes exhibited both membranous and nuclear p-β-catenin expression; hence, in the absence of Ras, progression stalled at wdSCC. Collectively, these data show that, in some contexts (hyperplasia/papillomas), E-cadherin loss can be tolerated via increased differentiation, while in carcinogenesis, following overt tumour appearance, conditional ablation of E-cadherin drives invasion and malignant progression, consistent with roles in cell–cell adhesion and deregulated signalling to β-catenin.