P53 protein levels are elevated by trastuzumab and the biologically similar rat ERBB2/HER2/NEU antibody; and that this coincides with enhanced apoptosis, increased cleaved caspase-3 levels and diminished cardiac function. We also demonstrate that MDM2 may be a regulatory target of anti-ERBB2 thereby implicating the MDM2/p53 axis as a potential molecular component for the undesirable cardiac outcomes noted with trastuzumab. Finally, we show that these MDM2/p53-mediated events are independent of both the ERK1/2 and Akt systems. In conclusion, our findings suggest that the adverse cardiac events observed with trastuzumab may stem from its negative regulation of MDM2 events which impairs p53 degradation resultantly promoting apoptosis leading to cardiac dysfunction. These observations may have important therapeutic implications since they suggest that anticancer agents that inhibit MDM2 and its downstream actions may curb tumor progression at the expense of increasing cardiac stress. (C) 2011 Elsevier Inc. All rights reserved.