title: p130Cas scaffold protein regulates ErbB2 stability by altering breast cancer cell sensitivity to autophagy.
abstract: 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.
authors.affiliation: Department of Biotechnology and Health Sciences, University of Torino, Torino, Italy.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Bisaro
authors.affiliation: Department of Biotechnology and Health Sciences, University of Torino, Torino, Italy.
authors.forename: Marianna
authors.initials: M
authors.lastname: Sciortino
authors.affiliation: Department of Biotechnology and Health Sciences, University of Torino, Torino, Italy.
authors.forename: Shana
authors.initials: S
authors.lastname: Colombo
authors.affiliation: Department of Biotechnology and Health Sciences, University of Torino, Torino, Italy.
authors.forename: Maria Pilar
authors.initials: MP
authors.lastname: Camacho Leal
authors.affiliation: Department of Biotechnology and Health Sciences, University of Torino, Torino, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Costamagna
authors.affiliation: Department of Medical Sciences, University of Torino, Torino, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Castellano
authors.affiliation: Investigative Clinical Oncology (INCO), Fondazione del Piemonte per l'Oncologia (FPO)-Candiolo Cancer Center (IRCCs), Torino, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Montemurro
authors.affiliation: Investigative Clinical Oncology (INCO), Fondazione del Piemonte per l'Oncologia (FPO)-Candiolo Cancer Center (IRCCs), Torino, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Rossi
authors.affiliation: Department of Oncology, University of Torino, Torino, Italy.|Department of Medical Sciences, University of Torino, Torino, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Valabrega
authors.affiliation: Department of Biotechnology and Health Sciences, University of Torino, Torino, Italy.
authors.forename: Emilia
authors.initials: E
authors.lastname: Turco
authors.affiliation: Department of Biotechnology and Health Sciences, University of Torino, Torino, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Defilippi
authors.affiliation: Department of Biotechnology and Health Sciences, University of Torino, Torino, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Cabodi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001343:Autophagy; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018275:Carcinoma, Lobular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D050719:Crk-Associated Substrate Protein / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D055550:Protein Stability; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000068878:Trastuzumab / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D050719:Crk-Associated Substrate Protein; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human
keywords: ErbB2; autophagy; breast cancer resistance; p130Cas