Trastuzumab (Herceptin®), a monoclonal antibody against the ErbB2 (HER2) 
receptor, has significantly improved clinical outcomes for HER2+ breast cancer 
patients. However, the drug also has known cardiotoxic side effects through 
mechanisms that are not fully understood. Here we utilized human induced 
pluripotent stem cell-derived cardiomyocytes (iPS-CMs) to model 
trastuzumab-related cardiotoxicity in vitro. We demonstrate that cardiotoxic 
effects of ErbB2 inhibition by trastuzumab can be recapitulated only when the 
cardioprotective effects of ErbB2/4 signaling is observed. We observed no 
cardioprotective effects of ErbB2/4 signaling without cellular stress 
(doxorubicin exposure in this study). In addition to neuregulin-1 (NRG-1), we 
show that heparin-binding epidermal growth factor-like growth factor (HB-EGF) 
also provides cardioprotective effects for iPS-CMs. Finally, we demonstrate a 
simple, high-throughput co-culture platform utilizing iPS-CMs and endothelial 
cells that is capable of detecting trastuzumab-related cardiotoxicity. We 
conclude that iPS-CMs can recapitulate trastuzumab-related cardiotoxicity, and 
may be used to elucidate additional modes of toxicity of trastuzumab and related 
compounds.