Can ErbB2 overexpression protect against doxorubicin cardiotoxicity?

IDENTIFICATION OF THE human epidermal growth factor receptor (HER2/ErbB2) as a target for therapy in HER2/ErbB2-positive breast cancer was a huge milestone in treatment of these typically highly aggressive cancers. At 8-yr follow-up, trastuzumab, a monoclonal antibody against HER2/ErbB2, increased survival by 40% compared with standard chemotherapy: anthracycline (doxorubicin), cyclophosphamide, and paclitaxel (11). Unfortunately, trastuzumab turned out to be severely cardiotoxic, leading to serious complications including left ventricular dysfunction and heart failure, with approximately three times greater incidence than anthracyclines (doxorubicin) alone (27 vs. 8% of patients at 1 yr of therapy) (14, 15). This is even further concerning when considering that anthracyclines themselves have considerable documented cardiotoxicity: 8% at 1 yr, 6-18% at 2 yr (4, 13), and 40% at 20 yr (5) postcompletion of treatment. As might be expected, because of the efficacy of anti-HER2/ErbB2 antibodies in the treatment of cancer, discovery of their cardiotoxicity prompted considerable research effort into mechanisms by which ErbB2 regulates cardiac function. For over a decade, it has been known that a major increase in oxidative stress was the primary mechanism of doxorubicinmediated cardiotoxicity (13). Oxidative stress has also been implicated as a mechanism for trastuzumab-induced cardiac dysfunction (6). ErbB2 antagonism in cardiac myocytes increased oxidative stress and cell death by increasing reactive oxygen species (ROS) and inducing mitochondrial apoptotic signaling (5). In this issue of the American Journal of Physiology-Heart and Circulatory Physiology, the study by Belmonte et. al. (1) extends these findings to demonstrate that cardiac-specific ErbB2 overexpression is able to upregulate mitochondrial antioxidant defenses (glutathione peroxidase-1 expression, glutathione peroxidase activity, and catalase expression) and downregulate hydrogen peroxide in the mitochondria. Mitochondrial oxidative stress plays a critical role in cardiovascular disease progression, including in the transition from compensatory hypertrophy to overt heart failure. Mitochondrial DNA (mtDNA) is more susceptible to damage by ROS due to lack of histones and thus greater accessibility to ROS and limited DNA repair enzyme capabilities in the mitochondria. Increased mtDNA damage translates into aberrant synthesis of proteins of the mitochondrial respiratory chain and eventual respiratory chain dysfunction (16). This then results in further ROS production, resulting in a cycle of amplification of ROS and mtDNA damage, which eventually leads to a critical drop in cellular ATP levels, Ca overload, and myocyte death. Thus discovering that ErbB2 specifically modulates mitochondrial ROS levels in the heart may be important since this may elucidate the mechanism by which ErbB2 regulates mitochondrial and cardiac dysfunction. In addition, the authors show that Abelson murine leukemia cellular oncogene homolog 1 (c-Abl) and Abelson-related gene (Arg) were upregulated by ErbB2 overexpression (1). c-Abl can transactivate the epidermal growth factor receptor through the Ras-Raf-extracellular signal recognition kinase 1/2 mitogen-activated protein kinase pathway as well as directly activate the phosphatidylinositol 3-kinase-Akt pathway (9), a major prosurvival signaling pathway in several cell types including cardiac myocytes. This is in agreement with the reported downregulation of Akt activation by ErbB2 antibodies in cancer cells and cardiac myocytes (5). Therefore, identification of these ErbB2-dependent signaling pathways in the heart in vivo are of potential translational significance with the goal of preserving cardiac function through decreasing myocyte cell death. There are limitations in extending the novel mechanistic aspects of the present study to the function and therapeutic targeting of this system in vivo, which will need to be investigated in future studies. First, the effects of ErbB2 overexpression on cardiotoxicity are not examined in adult cardiac myocytes or in the whole heart in vivo. Cardiotoxicity is instead evaluated in neonatal myocytes in cell culture. Neonatal and adult myocytes differ in many significant parameters relevant to cell survival, including sensitivity to altered Ca and ATP concentrations and oxygen consumption. Therefore, results from neonatal myocytes cannot be automatically translated to adult myocytes. Second, while this study shows that ErbB2 overexpression in the heart increases certain aspects of the cellular antioxidant defense machinery and reduces ROS, it remains to be demonstrated if it is able to achieve this effect in the face of a doxorubicin or anti-HER2/ErbB2 antibody challenge, i.e., if the ErbB2 overexpressing animals were treated with a chemotherapeutically effective dose of doxorubicin and/or trastuzumab, would ErbB2 overexpression still be able to prevent the increase in ROS? Third, this study demonstrates that ErbB2 overexpression maintains normal oxygen consumption and mitochondrial complex I activity. However, neither ATP production nor Ca concentrations was measured. Increased mitochondrial ROS production is frequently coupled to decreased ATP production. Mitochondrial ATP production has been shown to be decreased specifically in doxorubicin-induced heart failure (2). Decreased ATP production leads to Ca overload, mainly due to consequent failure of the sarcoplasmic reticulum Ca ATPase 2 and the Na /K ATPase leading to decreased activity of the Na /Ca exchanger, and heart failure. Therefore, it would be important to examine these parameters and cardiac function in future studies. In summary, based on the findings presented in this study, it is difficult to form definitive conclusions regarding the protective effect of HER2/ErbB2 overexpression in the heart against doxorubicinor trastuzumab-induced cardiotoxicity, either Address for reprint requests and other correspondence: P. Rocic, Dept. of Pharmacology, New York Medical College, School of Medicine, 15 Dana Rd., BSB 501, Valhalla, NY 10595 (e-mail: [email protected]). Am J Physiol Heart Circ Physiol 309: H1235–H1236, 2015; doi:10.1152/ajpheart.00647.2015. Editorial Focus