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

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.
Mesh Terms:
Animals, Breast Neoplasms, Cadherins, Cell Line, Tumor, Cell Movement, Cell Survival, Disease-Free Survival, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Mice, Mice, Nude, Neoplasm Grading, Neoplasm Invasiveness, Prognosis, RNA Interference, RNA, Messenger, Signal Transduction, Time Factors, Transfection, Tumor Burden
J. Pathol.
Date: Apr. 01, 2013
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