Conditional mutation of the ErbB2 (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathy

Abstract

The ErbB2 (Her2) proto-oncogene encodes a receptor tyrosine kinase, which is frequently amplified and overexpressed in human tumors. ErbB2 provides the target for a novel and effective antibody-based therapy (Trastuzumab͞Herceptin) used for the treatment of mammary carcinomas. However, cardiomyopathies develop in a proportion of patients treated with Trastuzumab, and the incidence of such complications is increased by combination with standard chemotherapy. Gene ablation studies have previously demonstrated that the ErbB2 receptor, together with its coreceptor ErbB4 and the ligand Neuregulin-1, are essential for normal development of the heart ventricle. We use here Cre-loxP technology to mutate ErbB2 specifically in ventricular cardiomyocytes. Conditional mutant mice develop a severe dilated cardiomyopathy, with signs of cardiac dysfunction generally appearing by the second postnatal month. We infer that signaling from the ErbB2 receptor, which is enriched in T-tubules in cardiomyocytes, is crucial for adult heart function. Conditional ErbB2 mutant mice provide a model of dilated cardiomyopathy. In particular, they will allow a rigorous assessment of the role of ErbB2 in the heart and provide insight into the molecular mechanisms that underlie the adverse effects of anti-ErbB2 antibodies.

The epidermal growth factor receptor family: Biology driving targeted therapeutics

“…Our understanding of the biology of ErbB2 in mouse models has also been predictive of side effects of ErbB2 inhibition. Consistent with the cardiomyopathy seen in mice lacking myocardial ErbB2 [121,122], one complication of trastuzumab is the development of a reversible cardiomyopathy often with congestive heart failure in approximately 3 % of patients [168].…”

“…Mice lacking ErbB2 die at mid-gestation likely due to failure of cardiac trabeculae formation [119,120]. Conditional deletion of ErbB2 in the ventricular myocardium of mice leads to postnatal dilated cardiomyopathy and death [121,122]. In addition, mice deficient in ErbB2 show defects in cranial sensory ganglia likely due to defects in cranial neural crest [119,123].…”

“…Table 1 ErbB receptor-ligand binding specificity. [125,126] Ventricular cardiomyocyte specific deletion Dilated cardiomyopathy Cardiomyocyte sensitivity to anthracycline toxicity [121,122] Cell Mol Life Sci. Author manuscript; available in PMC 2011 March 17.…”

Cardiotoxicity From Human Epidermal Growth Factor Receptor‐2 (HER2) Targeted Therapies

“…In response to the ligand, neuregulin‐1, ErbB2 forms heterodimers that activate cell hypertrophy and survival pathways through activation of the phosphoinositide 3‐kinase and protein kinase A pathways as well as the mitogen‐activated protein kinase cascade 60, 63. In murine models, deletion of ErbB2 leads to development of spontaneous dilated cardiomyopathy and makes these mice more sensitive to triggers of cardiomyopathy such as pressure overload and anthracyclines 64, 65. Taken together, this evidence suggests an important role of ErbB2 in the maintenance of normal cardiac structure and function, especially under stress conditions.…”

Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity

“…The mechanisms of action of trastuzumab are complex and not fully understood. Described mechanisms include receptor downregulation (Sliwkowski et al, 1999;Ozcelik et al, 2002;Diermeier et al, 2005;Yuste et al, 2005), cell cycle arrest (Kim et al, 2003), inhibition of angiogenesis (Izumi et al, 2002) and induction of antibody-dependent cell-mediated cytotoxicity (ADCC) (Clynes et al, 2000).…”