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HER2-driven mammary tumorigenesis enhances bioenergetics despite reductions in mitochondrial content

Sara M Frangos1, Henver S Brunetta1, Dongdong Wang2,3

  • 1Department of Human Health Sciences, University of Guelph, Guelph, Canada.

Elife
|May 6, 2026
PubMed

Insights

Mitochondria are key in cancer, but tumor metabolism varies. This study found higher mitochondrial respiration in HER2-positive breast tumors than expected, suggesting HER2 signaling drives this bioenergetic shift.

Area of Science:

  • Oncology
  • Mitochondrial Biology
  • Cancer Metabolism

Background:

  • Mitochondria are crucial in tumorigenesis, but tumor metabolism differs across cancer types.
  • Previous attempts to target tumor respiration via oxidative phosphorylation inhibitors have failed.
  • Understanding mitochondrial bioenergetics in diverse tumors is critical.

Purpose of the Study:

  • To comprehensively assess the metabolic phenotype of mitochondria in murine HER2-driven mammary cancer.
  • To investigate the relationship between mitochondrial content and respiratory capacity in tumors.
  • To explore the role of HER2 signaling in regulating mitochondrial bioenergetics.

Main Methods:

  • Transcriptomic and proteomic profiling of murine HER2-driven mammary tumors and benign mammary tissue.
  • Measurement of mitochondrial respiration using various normalization methods.
  • Assessment of the effect of lapatinib (EGFR/HER2 inhibitor) on mitochondrial respiration in tumor cells.

Main Results:

  • Tumors showed downregulation of mitochondrial genes and proteins, including oxidative phosphorylation (OXPHOS) subunits.
  • Despite reduced mitochondrial proteins, tumor mitochondrial respiration was significantly higher than in benign tissue.
  • This increased respiration was not due to OXPHOS uncoupling and was attenuated by lapatinib treatment.

Conclusions:

  • The correlation between mitochondrial content and respiratory capacity may not hold true for all tumor types.
  • HER2 signaling appears to intrinsically regulate mitochondrial bioenergetics, enhancing respiration.
  • HER2-linked activation of mitochondrial respiration supports tumorigenesis in this model.
Keywords:
HER2bioenergeticscancer biologycancer metabolismcell biologymitochondriamouseproteomicstranscriptomics

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