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.

Ado-Trastuzumab Emtansine Targets Hepatocytes Via Human Epidermal Growth Factor Receptor 2 to Induce Hepatotoxicity

“…A B D C induced cardiotoxicity is HER2 dependent (25)(26)(27)(28)(29). We used both cellular and mouse model systems to investigate a clinically relevant case of drug-induced hepatotoxicity and to elucidate the possible mechanisms of T-DM1-induced hepatotoxicity.…”

“…Murine model has been widely used to study the mechanisms of trastuzumab-induced cardiotoxicity (25)(26)(27)(28)(29). Riccio and colleagues have shown that trastuzumab binds to mouse HER2 (26) and that mice treated with trastuzumab have reduced left ventricular ejection fraction (25)(26)(27)(28)(29).…”

“…Riccio and colleagues have shown that trastuzumab binds to mouse HER2 (26) and that mice treated with trastuzumab have reduced left ventricular ejection fraction (25)(26)(27)(28)(29). Trastuzumab may directly block antiapoptotic signaling, leading to premature cardiac dysfunction (28).…”

“…Trastuzumab may directly block antiapoptotic signaling, leading to premature cardiac dysfunction (28). Although HER2 is present at a low level in mouse cardiomyocytes, the studies from different laboratories suggested that trastuzumab-induced cardiotoxicity may be HER2-dependent (25)(26)(27)(28)(29). Furthermore, trastuzumab treatment induces apoptosis in cardiac sections of heart tissues from mice treated with trastuzumab (25,28).…”

Trastuzumab, but Not Pertuzumab, Dysregulates HER2 Signaling to Mediate Inhibition of Autophagy and Increase in Reactive Oxygen Species Production in Human Cardiomyocytes

“…Using C57BL/6 mouse model, we have previously reported that trastuzumab treatment induced alteration in myocardial expression of genes that are critically involved in cardiac and mitochondrial functions, adaptation to stress, and DNA repair (12). We observed that these genetic changes are associated with increased myocardial oxidative and nitrative stress, and potentially activated apoptotic pathways, leading to elevated serum troponin-1 and cardiac myosin light chain-1 (cMLC1) levels (12).…”