p130Cas scaffold protein regulates ErbB2 stability by altering breast cancer cell sensitivity to autophagy
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Brigitte Bisaro1, Marianna Sciortino1, Shana Colombo1, Maria Pilar Camacho Leal1, Andrea Costamagna1, Isabella Castellano2, Filippo Montemurro3, Valentina Rossi3, Giorgio Valabrega4,2, Emilia Turco1, Paola Defilippi1, Sara Cabodi1
1Department of Biotechnology and Health Sciences, University of Torino, Torino, Italy
2Department of Medical Sciences, University of Torino, Torino, Italy
3Investigative Clinical Oncology (INCO), Fondazione del Piemonte per l'Oncologia (FPO)-Candiolo Cancer Center (IRCCs), Torino, Italy
4Department of Oncology, University of Torino, Torino, Italy
Sara Cabodi, e-mail: [email protected]
Keywords: p130Cas, ErbB2, autophagy, breast cancer resistance
Received: June 16, 2015 Accepted: November 25, 2015 Published: December 21, 2015
Overexpression of the ErbB2/HER2 receptor tyrosine kinase occurs in up to 20% of human breast cancers and correlates with aggressive disease. Several efficacious targeted therapies, including antibodies and kinase inhibitors, have been developed but the occurring of resistance to these agents is often observed. New therapeutic agents targeting the endocytic recycling and intracellular trafficking of membrane in tumor cells overexpressing ErbB2 are actually in clinical development. Nevertheless the mechanisms underlying ErbB2 downregulation are still obscure. We have previously demonstrated that the overexpression of the p130Cas adaptor protein in ErbB2 positive breast cancer, promotes tumor aggressiveness and progression. Here we demonstrate that lowering p130Cas expression in breast cancer cells is sufficient to induce ErbB2 degradation by autophagy. Conversely, p130Cas overexpression protects ErbB2 from degradation by autophagy. Furthermore, this autophagy-dependent preferential degradation of ErbB2 in absence of p130Cas is due to an increased ErbB2 ubiquitination. Indeed, the overexpression of p130Cas impairs ErbB2 ubiquitination by inhibiting the binding of Cbl and CHIP E3 ligases to ErbB2. Finally, our results indicate that p130Cas-dependent ErbB2 protection from degradation by autophagy may alter the sensitivity to the humanized monoclonal antibody trastuzumab. Consistently, in human ErbB2 positive breast cancers that develop resistance to trastuzumab, p130Cas expression is significantly increased suggesting that elevated levels of p130Cas can be involved in trastuzumab resistance.
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