title: ERBB2 deficiency alters an E2F-1-dependent adaptive stress response and leads to cardiac dysfunction.
abstract: The tyrosine kinase receptor ERBB2 is required for normal development of the heart and is a potent oncogene in breast epithelium. Trastuzumab, a monoclonal antibody targeting ERBB2, improves the survival of breast cancer patients, but cardiac dysfunction is a major side effect of the drug. The molecular mechanisms underlying how ERBB2 regulates cardiac function and why trastuzumab is cardiotoxic remain poorly understood. We show here that ERBB2 hypomorphic mice develop cardiac dysfunction that mimics the side effects observed in patients treated with trastuzumab. We demonstrate that this phenotype is related to the critical role played by ERBB2 in cardiac homeostasis and physiological hypertrophy. Importantly, genetic and therapeutic reduction of ERBB2 activity in mice, as well as ablation of ERBB2 signaling by trastuzumab or siRNAs in human cardiomyocytes, led to the identification of an impaired E2F-1-dependent genetic program critical for the cardiac adaptive stress response. These findings demonstrate the existence of a previously unknown mechanistic link between ERBB2 and E2F-1 transcriptional activity in heart physiology and trastuzumab-induced cardiac dysfunction.
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Quebec, Canada Department of Biochemistry, McGill University, Montréal, Quebec, Canada.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Perry
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Quebec, Canada.
authors.forename: Catherine R
authors.initials: CR
authors.lastname: Dufour
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Quebec, Canada Department of Biochemistry, McGill University, Montréal, Quebec, Canada.
authors.forename: Lillian J
authors.initials: LJ
authors.lastname: Eichner
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Quebec, Canada Department of Biochemistry, McGill University, Montréal, Quebec, Canada.
authors.forename: David W K
authors.initials: DW
authors.lastname: Tsang
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Quebec, Canada Department of Biochemistry, McGill University, Montréal, Quebec, Canada.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Deblois
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Quebec, Canada Department of Biochemistry, McGill University, Montréal, Quebec, Canada Department of Medicine and Oncology, McGill University, Montréal, Quebec, Canada.
authors.forename: William J
authors.initials: WJ
authors.lastname: Muller
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Quebec, Canada Department of Biochemistry, McGill University, Montréal, Quebec, Canada Department of Medicine and Oncology, McGill University, Montréal, Quebec, Canada vincentgiguere@mcgill.ca.
authors.forename: Vincent
authors.initials: V
authors.lastname: Giguère
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology; D006332:Cardiomegaly / Q000235:genetics*; D002478:Cells, Cultured; D004317:Doxorubicin / Q000009:adverse effects / Q000494:pharmacology; D050687:E2F1 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004452:Echocardiography; D005355:Fibrosis; D020869:Gene Expression Profiling; D055879:Gene Knock-In Techniques; D006321:Heart / Q000254:growth & development; D006801:Humans; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects*; D034622:RNA Interference; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics; D013312:Stress, Physiological; D013318:Stroke Volume / Q000235:genetics; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D004317:Doxorubicin; D050687:E2F1 Transcription Factor; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C493754:E2f1 protein, mouse; C524056:Erbb2 protein, mouse