Essential Roles of Her2/erbB2 in Cardiac Development and Function

Abstract

The tyrosine kinase receptor erbB2, also known in humans as Her2, is a member of the epidermal growth factor receptor (EGFR or erbB1) family, which also includes erbB3 and erbB4. The erbBs were discovered in an avian erythroblastosis tumor virus and exhibited similarities to human EGFR (Yarden and Sliwkowski, 2001). Her2/erbB2 is highly expressed in many cancer types. Its overexpression is correlated with a poor prognosis for breast and ovarian cancer patients. ErbB receptors bind to a family of growth factors, termed neuregulins/heregulin (NRG/HRG), which comprise NRG-1, -2, -3, and -4 and include multiple isoforms. ErbB2/Her2 is an orphan receptor that does not bind ligand alone but heterodimerizes with the other erbB receptors for NRG signaling. ErbB2 is expressed in multiple neuronal and non-neuronal tissues in embryos and adult animals, including the heart. Genetic data demonstrated that erbB2 is required for normal embryonic development of neural crest-derived cranial sensory neurons. ErbB2/Her2-null mutant embryos of a trabeculation defect die before embryonic day (E) 11. To study its role at later stages of development, we generated a transgenic mouse line that specifically expresses the rat erbB2 cDNA in the heart under the control of the cardiac-specific ␣-myosin heavy chain promoter. When crossed into the null background, the expression of the rat erbB2 cDNA rescued the cardiac phenotype in the erbB2-null mutant mice that survive until birth but display an absence of Schwann cells and a severe loss of both motor and spinal sensory neurons. To study the role of erbB2 in the adult heart, we generated conditional mutant mice carrying a cardiac-restricted deletion of erbB2. These erbB2 conditional mutants exhibited multiple independent parameters of dilated cardiomyopathy, including chamber dilation, wall thinning, and decreased contractility. Interestingly, treatment of breast cancers overexpressing erbB2 with Herceptin (Trastuzumab), a humanized monoclonal antibody specific to the extracellular domain of erbB2, results in some patients developing cardiac dysfunction. The adverse effect is increased significantly in those patients who also receive the chemotherapeutical agent anthracycline. We found that erbB2-deficient cardiac myocytes are more susceptible to anthracyclineinduced cytotoxicity. These results suggest that erbB2 signaling in the heart is essential for the prevention of dilated cardiomyopathy. These lines of mice provide models with which to elucidate the molecular and cellular mechanisms by which erbB2 signaling regulates cardiac functions. These mice also will provide important information for devising strategies to mitigate the cardiotoxic effects of Herceptin treatment, allowing for the potential expanded use of this drug to treat all cancers overexpressing erbB2.

Reorganization of ErbB Family and Cell Survival Signaling after Knock-down of ErbB2 in Colon Cancer Cells

“…have been developed to target specifically tumor cells expressing ErbB2 oncoprotein. These strategies include chemical inhibitors (61), dominant kinase-negative mutants (38,62), monoclonal antibodies (63,64), and antisense gene inhibition (65). However, these strategies have been focused mainly on ErbB2 overexpressing tumor cells.…”

“…Gene amplification and overexpression of ErbB2 are correlated with poor prognosis in breast and ovarian cancer (37,38), but the role of ErbB2 in colon cancer is largely unknown. Our work has suggested a role for ErbB2 in colon cancer because coexpression of ErbB2 and heregulin in colon tumors and cell lines was demonstrated, indicating that constitutive activation of "normal" levels of ErbB2 could provide the signaling basis of tumor growth (39).…”

A Negative Feedback Regulatory Loop Associates the Tyrosine Kinase Receptor ERBB2 and the Transcription Factor GATA4 in Breast Cancer Cells

“…In one study, the gene encoding the transcription factor GATA4 was identified as one of the 29 overexpressed genes differentially expressed in tumors associated with ERBB2 overexpression (24,25). Interestingly, ERBB2 and GATA4 are essential for cardiovascular development (26)(27)(28) and it has been proposed that GATA4 controls the transcription of critical genes for both differentiation and function of the myocardium. The transcriptional activity of GATA4 is activated via the mitogen-activated protein kinase pathway in cardiomyocytes (29) and the ERBB2 receptor triggers several transduction pathways including the mitogenactivated protein kinase pathway (2).…”

Trastuzumab and Cardiotoxicity

“…These free radicals produce peroxidation of myocyte membranes and subsequent influx of intracellular calcium, accelerated degradation of key sarcomeric protein and disruption of new sarcomere protein synthesis. (Valero, 2004; The molecular basis of type II chemotherapy related cardiac dysfunction is beginning to be elucidated (Speyer, 2002;Crone, 2002;Ozcelik, 2002;Sawyer, 2002;Negro, 2004). The mechanism of trastuzumab induced cardiotoxicity involves, at least in part, the ErbB2 pathway.…”

“…This agent binds to the extracellular domain of the HER-2 protein and thus blocks ErbB2 signalling required for the growth, repair, and survival of cardiac cells. (Negro, 2004) ErbB2 signalling is highly complex, involving multiple ligand classes, cell systems, and pathway interactions. Of those actions, activation of the transcription factor nuclear-B (NF-B) seems to play an important rule.…”