title: Trastuzumab alters the expression of genes essential for cardiac function and induces ultrastructural changes of cardiomyocytes in mice.
abstract: Treatment with trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of Human Epidermal Growth Factor Receptor 2 (HER2), very successfully improves outcomes for women with HER2-positive breast cancer. However, trastuzumab treatment was recently linked to potentially irreversible serious cardiotoxicity, the mechanisms of which are largely elusive. This study reports that trastuzumab significantly alters the expression of myocardial genes essential for DNA repair, cardiac and mitochondrial functions, which is associated with impaired left ventricular performance in mice coupled with significant ultrastructural alterations in cardiomyocytes revealed by electron microscopy. Furthermore, trastuzumab treatment also promotes oxidative stress and apoptosis in myocardium of mice, and elevates serum levels of cardiac troponin-I (cTnI) and cardiac myosin light chain-1 (cMLC1). The elevated serum levels of cMLC1 in mice treated with trastuzumab highlights the potential that cMLC1 could be a useful biomarker for trastuzumab-induced cardiotoxicity.
authors.affiliation: Division of Monoclonal Antibodies, Office of Biotechnology Products, Office of Pharmaceutical Science, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Bethesda, Maryland, United States of America ; Interagency Oncology Task Force (IOTF) Fellowship: Program 4 - Cancer Prevention Fellow, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: M Khair
authors.initials: MK
authors.lastname: ElZarrad
authors.forename: Partha
authors.initials: P
authors.lastname: Mukhopadhyay
authors.forename: Nishant
authors.initials: N
authors.lastname: Mohan
authors.forename: Enkui
authors.initials: E
authors.lastname: Hao
authors.forename: Milos
authors.initials: M
authors.lastname: Dokmanovic
authors.forename: Dianne S
authors.initials: DS
authors.lastname: Hirsch
authors.forename: Yi
authors.initials: Y
authors.lastname: Shen
authors.forename: Pal
authors.initials: P
authors.lastname: Pacher
authors.forename: Wen Jin
authors.initials: WJ
authors.lastname: Wu
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects*; D017209:Apoptosis / Q000235:genetics; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics; D006321:Heart / Q000187:drug effects* / Q000502:physiology*; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D006439:Hemodynamics / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics; D009119:Muscle Contraction / Q000187:drug effects / Q000235:genetics; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure*; D018994:Myosin Light Chains / Q000097:blood; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000187:drug effects; D013312:Stress, Physiological / Q000187:drug effects / Q000235:genetics; D059467:Transcriptome / Q000187:drug effects*; D000068878:Trastuzumab; D019210:Troponin I / Q000097:blood
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018994:Myosin Light Chains; D019210:Troponin I; D053148:Caspase 3; D053179:Caspase 7; D000068878:Trastuzumab