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

Abstract

Functional oncogenic links between ErbB2 and ERRα in HER2+ breast cancer patients support a therapeutic benefit of co-targeted therapies. However, ErbB2 and ERRα 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 ERRα 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 ERRα 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.

Mammary Glands of Women, Female Dogs and Female Rats: Similarities and Differences to Be Considered in Breast Cancer Research

“…After tumor diagnosis, this close follow-up allows several types of data to be obtained, such as overall incidence, latency and multiplicity (i.e., number of tumors per rat) [ 103 ]. At the end of the experiment, mammary tumors are collected, weighed, and stored/processed for various analyses, including histopathology [ 103 ] and omics-based analysis [ 204 , 205 ], among others. Lastly, the use of female rats as a mammary cancer model must be approved by the appropriate authorities for the protection of animals used for scientific purposes, and all legal aspects should be respected [ 5 ].…”