Integrated multi-omics analysis of adverse cardiac remodeling and metabolic inflexibility upon ErbB2 and ERRα deficiency

Functional oncogenic links between ErbB2 and ERR alpha in HER2+ breast cancer patients support a therapeutic benefit of co-targeted therapies. However, ErbB2 and ERR alpha also play key roles in heart physiology, and this approach could pose a potential liability to cardiovascular health. Herein, using integrated phosphoproteomic, transcriptomic and metabolic profiling, we uncovered molecular mechanisms associated with the adverse remodeling of cardiac functions in mice with combined attenuation of ErbB2 and ERR alpha activity. Genetic disruption of both effectors results in profound effects on cardiomyocyte architecture, inflammatory response and metabolism, the latter leading to a decrease in fatty acyl-carnitine species further increasing the reliance on glucose as a metabolic fuel, a hallmark of failing hearts. Furthermore, integrated omics signatures of ERR alpha loss-of-function and doxorubicin treatment exhibit common features of chemotherapeutic cardiotoxicity. These findings thus reveal potential cardiovascular risks in discrete combination therapies in the treatment of breast and other cancers. Murine hearts deficient in ErbB2 and/or ERR alpha are used to profile the adverse cardiac remodeling associated with potential targeted breast cancer treatments by phosphoproteomic, transcriptomic and metabolomic profiling.

Automated summary

This study reveals the adverse cardiac remodeling associated with potential targeted breast cancer treatments by using murine hearts deficient in ErbB2 and/or ERR alpha. The findings suggest potential cardiovascular risks in discrete combination therapies in the treatment of breast and other cancers.