P‐cadherin functional role is dependent on E‐cadherin cellular context: a proof of concept using the breast cancer model

Abstract

P-cadherin overexpression is associated with worse breast cancer survival, being a poor prognostic marker as well as a putative therapeutic target for the aggressive triple-negative and basal-like carcinomas (TNBCs). Previously, we have shown that P-cadherin promotes breast cancer invasion of cells where membrane E-cadherin was maintained; however, it suppresses invasion in models without endogenous cadherins, like melanomas. Here, we investigated if P-cadherin expression would interfere with the normal adhesion complex and which were the cellular/molecular consequences, constituting, in this way, a new mechanism by which E-cadherin invasive-suppressor function was disrupted. Using breast TNBC models, we demonstrated, for the first time, that P-cadherin co-localizes with E-cadherin, promoting cell invasion due to the disruption caused in the interaction between E-cadherin and cytoplasmic catenins. P-cadherin also induces cell migration and survival, modifying the expression profile of cells expressing wild-type E-cadherin and contributing to alter their cellular behaviour. Additionally, E- and P-cadherin co-expressing cells significantly enhanced in vivo tumour growth, compared with cells expressing only E- or only P-cadherin. Finally, we still found that co-expression of both molecules was significantly correlated with high-grade breast carcinomas, biologically aggressive, and with poor patient survival, being a strong prognostic factor in this disease. Our results show a role for E- and P-cadherin co-expression in breast cancer progression and highlight the potential benefit of targeting P-cadherin in the aggressive tumours expressing high levels of this protein.

Cell adhesion and urothelial bladder cancer: the role of cadherin switching and related phenomena

“…For example, in malignant melanoma, which commonly demonstrates a cadherin switch to N-cadherin expression [22], P-cadherin promotes adhesion and inhibits invasion in a similar fashion to E-cadherin [74], and E-cadherin negative breast cancer cells show many similarities when subsequently transfected with E-or P-cadherin [73,92]. Ribeiro et al [93] investigated these phenomena in detail in a breast cancer model, demonstrating that P-cadherin co-localizes with E-cadherin, and promotes cell invasion by disrupting E-cadherin/catenin interactions. E-and P-cadherin co-expressing tumour cells showed enhanced in vivo tumour growth compared with those expressing only E-or only P-cadherin, and co-expression of E-and P-cadherin in breast tumours correlated with high-grade biologically aggressive tumours accompanied by poor patient survival [93].…”

“…Ribeiro et al [93] investigated these phenomena in detail in a breast cancer model, demonstrating that P-cadherin co-localizes with E-cadherin, and promotes cell invasion by disrupting E-cadherin/catenin interactions. E-and P-cadherin co-expressing tumour cells showed enhanced in vivo tumour growth compared with those expressing only E-or only P-cadherin, and co-expression of E-and P-cadherin in breast tumours correlated with high-grade biologically aggressive tumours accompanied by poor patient survival [93]. It is therefore feasible that P-cadherin only promotes invasion in tissues that endogenously express E-cadherin [73], with heterodimerization between E-and P-cadherin disrupting the formation of functional cadherin-catenin complexes [74].…”

Epithelioid peritoneal mesothelioma: a hybrid phenotype within a mesenchymal-epithelial/epithelial-mesenchymal transition framework

“…It has been reported that, in addition to mediating intracellular cohesion, E-cadherin participates in regulating stemness [19–21], and the same is true for c-MYC [22, 23]. The recently described co-expression of E- and P-cadherin is particularly interesting as it has been reported to be a marker of stemness [24] or related to poor prognosis [25], and can be seen in the hybrid state of EMT/MErT [6, 7, 24]. …”

Cadherins in Cancer

“…14.3). Additionally, it has been reported that P-cadherin expression can lead to the distortion of E-cadherin function and the downregulation of its expression (Paredes et al 2008;Cheung et al 2010;Van Marck et al 2011;Jacobs et al 2011;Cheung et al 2011;Sun et al 2011;Vlahova et al 2012;Ribeiro et al 2013;Thuault et al 2013).…”