ArticleCancer research2016
The Ephrin-A1/EPHA2 Signaling Axis Regulates Glutamine Metabolism in HER2-Positive Breast Cancer.
Article in Cancer research, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers.
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Who cites it
56 citing papers in PubMed, 83 citations in OpenAlex.
- EphA2 as an oncogenic driver: roles and mechanisms of action in cancer.Molecular biology reports · 2026Review
- Regulation of Amino Acid Transporters by Cell Surface Receptors.Antioxidants (Basel, Switzerland) · 2026Review
- Cancer Neoaxonogenesis: Mechanisms and Factors Involved in the Recruitment of Peripheral Nerves by Cancer Tissue.International journal of molecular sciences · 2026Review
- Cetuximab co-treatment with KRAS G12C inhibitors fulzerasib and sotorasib in human KRAS G12C non-small cell lung cancer cells.Cell death discovery · 2026Article
- Metabolic hallmarks of trastuzumab resistance.Expert opinion on therapeutic targets · 2025Review
- Immunohistochemical determination of the expression of Eph receptors in lipid-rich variation of experimental rat mammary carcinomas.Journal of molecular histology · 2025Article
- Integrated spatial omics of metabolic reprogramming and the tumor microenvironment in pancreatic cancer.iScience · 2025Article
- Glutamate promotes triple-negative breast cancer development through IRE1α/XBP1-mediated macrophage polarization: mechanism insights and therapy.Discover oncology · 2025Article
- Development of an anti-human EphA2 monoclonal antibody EaBiochemistry and biophysics reports · 2025Article
- Review
- Suppressing glutamine metabolism in the pancreatic cancer microenvironment can enhance the anti-tumor effect of CD8 T cells and promote the efficacy of immunotherapy.Frontiers in immunology · 2025Article
- Delivery-Graded Programmable Micelles Achieve Enhanced Tumor Starvation through Combined Glutamine Deprivation and Angiogenesis Inhibition.Research (Washington, D.C.) · 2025Article
- The diagnostic value of serum Ephrin-A1 in patients with colorectal cancer.Scientific reports · 2024Article
- Transmembrane Amino Acid Transporters in Shaping the Metabolic Profile of Breast Cancer Cell Lines: The Focus on Molecular Biological Subtype.Current issues in molecular biology · 2024Review
- Advancing Anticancer Drug Discovery: Leveraging Metabolomics and Machine Learning for Mode of Action Prediction by Pattern Recognition.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Serum EphA2 as a Promising Biomarker for the Early Detection and Diagnosis of Colorectal Cancer.Biomolecules · 2024Article
- The Use of Patient-Derived Organoids in the Study of Molecular Metabolic Adaptation in Breast Cancer.International journal of molecular sciences · 2024Review
- A prismatic view of the epigenetic-metabolic regulatory axis in breast cancer therapy resistance.Oncogene · 2024Review
- Elucidating the Role of Wildtype and Variant FGFR2 Structural Dynamics in (Dys)Function and Disorder.International journal of molecular sciences · 2024Article
- Targeting EphA2: a promising strategy to overcome chemoresistance and drug resistance in cancer.Journal of molecular medicine (Berlin, Germany) · 2024Review
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
Dysregulation of receptor tyrosine kinases (RTK) contributes to cellular transformation and cancer progression by disrupting key metabolic signaling pathways. The EPHA2 RTK is overexpressed in aggressive forms of breast cancer, including the HER2(+) subtype, and correlates with poor prognosis. However, the role of EPHA2 in tumor metabolism remains unexplored. In this study, we used in vivo and in vitro models of HER2-overexpressing breast cancer to investigate the mechanisms by which EPHA2 ligand-independent signaling promotes tumorigenesis in the absence of its prototypic ligand, ephrin-A1. We demonstrate that ephrin-A1 loss leads to upregulated glutamine metabolism and lipid accumulation that enhanced tumor growth. Global metabolic profiling of ephrin-A1-null, HER2-overexpressing mammary tumors revealed a significant increase in glutaminolysis, a critical metabolic pathway that generates intermediates for lipogenesis. Pharmacologic inhibition of glutaminase activity reduced tumor growth in both ephrin-A1-depleted and EPHA2-overexpressing tumor allografts in vivo Mechanistically, we show that the enhanced proliferation and glutaminolysis in the absence of ephrin-A1 were attributed to increased RhoA-dependent glutaminase activity. EPHA2 depletion or pharmacologic inhibition of Rho, glutaminase, or fatty acid synthase abrogated the increased lipid content and proliferative effects of ephrin-A1 knockdown. Together, these findings highlight a novel, unsuspected connection between the EPHA2/ephrin-A1 signaling axis and tumor metabolism, and suggest potential new therapeutic targets in cancer subtypes exhibiting glutamine dependency. Cancer Res; 76(7); 1825-36. ©2016 AACR.
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