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Updated: Aug 29, 2025
Assessing Cardiac Reprogramming using High Content Imaging Analysis
Published on: October 26, 2020
Integrated multi-omics analysis of adverse cardiac remodeling and metabolic inflexibility upon ErbB2 and ERRα
Catherine R Dufour1, Hui Xia1,2, Wafa B'chir1
1Goodman Cancer Institute, McGill University, Montréal, QC, H3A 1A3, Canada.
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.
Insights
Targeting ErbB2 and ERRα in HER2+ breast cancer may harm heart function. Combined ErbB2 and ERRα inhibition in mice caused cardiac remodeling, altered metabolism, and revealed shared mechanisms with chemotherapy cardiotoxicity.
Area of Science:
- Cardiovascular Biology
- Oncology
- Metabolomics
Background:
- Estrogen-related receptor alpha (ERRα) and ErbB2 signaling are implicated in HER2+ breast cancer.
- Co-targeting ErbB2 and ERRα may offer therapeutic benefits but poses cardiovascular risks due to their roles in heart physiology.
Purpose of the Study:
- To investigate the molecular mechanisms underlying adverse cardiac remodeling from combined ErbB2 and ERRα inhibition.
- To identify potential cardiovascular liabilities associated with co-targeted therapies in cancer treatment.
Main Methods:
- Integrated phosphoproteomic, transcriptomic, and metabolic profiling in mice with combined ErbB2 and ERRα activity attenuation.
- Analysis of cardiomyocyte architecture, inflammatory response, and metabolic pathways.
Main Results:
- Combined ErbB2 and ERRα disruption led to significant cardiac remodeling, affecting cardiomyocyte structure and inflammatory responses.
- Metabolic profiling revealed decreased fatty acyl-carnitine species and increased glucose reliance, indicative of heart failure.
- Integrated omics signatures showed commonalities between ERRα loss-of-function, doxorubicin treatment, and chemotherapeutic cardiotoxicity.
Conclusions:
- Combined ErbB2 and ERRα inhibition can induce adverse cardiac remodeling and metabolic dysfunction.
- These findings highlight potential cardiovascular risks associated with co-targeting strategies in cancer therapy.
- Understanding these mechanisms is crucial for developing safer combination therapies for breast and other cancers.
