P‐cadherin functional role is dependent on E‐cadherin cellular context: a proof of concept using the breast cancer model |
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Authors: | Ana Sofia Ribeiro Bárbara Sousa Laura Carreto Nuno Mendes Ana Rita Nobre Sara Ricardo André Albergaria Jorge F Cameselle‐Teijeiro Rene Gerhard Ola Söderberg Raquel Seruca Manuel A Santos Fernando Schmitt Joana Paredes |
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Institution: | 1. IPATIMUP, Institute of Molecular Pathology and Immunology of the University of Porto, , Porto, Portugal;2. ICBAS – Abel Salazar Biomedical Science Institute, , Porto, Portugal;3. Department of Biology and CESAM, University of Aveiro, , Aveiro, Portugal;4. Complexo Hospitalar Universitario de Vigo (CHUVI), , Vigo, Spain;5. Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, , Uppsala, Sweden;6. Medical Faculty of the University of Porto, , Porto, Portugal |
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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. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. |
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Keywords: | P‐cadherin E‐cadherin invasion motility breast cancer |
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