title: The Ephrin-A1/EPHA2 Signaling Axis Regulates Glutamine Metabolism in HER2-Positive Breast Cancer.
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.
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Youngblood
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Kim
authors.affiliation: Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: Deanna N
authors.initials: DN
authors.lastname: Edwards
authors.affiliation: Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University, Nashville, Tennessee. Veterans Affairs Medical Center, Tennessee Valley Healthcare System, Nashville, Tennessee.
authors.forename: Yoonha
authors.initials: Y
authors.lastname: Hwang
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Pranav R
authors.initials: PR
authors.lastname: Santapuram
authors.affiliation: Metabolon Inc., Durham, North Carolina.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Stirdivant
authors.affiliation: Department of Biostatistics, Vanderbilt University, Nashville, Tennessee.
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Lu
authors.affiliation: Department of Biostatistics, Vanderbilt University, Nashville, Tennessee.
authors.forename: Fei
authors.initials: F
authors.lastname: Ye
authors.affiliation: Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University, Nashville, Tennessee. Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee. jin.chen@vanderbilt.edu dana.brantley@vanderbilt.edu.
authors.forename: Dana M
authors.initials: DM
authors.lastname: Brantley-Sieders
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee. Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University, Nashville, Tennessee. Veterans Affairs Medical Center, Tennessee Valley Healthcare System, Nashville, Tennessee. Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee. Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee. jin.chen@vanderbilt.edu dana.brantley@vanderbilt.edu.
authors.forename: Jin
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation; D036382:Ephrin-A1 / Q000378:metabolism*; D005260:Female; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D051379:Mice; D036104:Receptor, EphA2 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D036382:Ephrin-A1; D005973:Glutamine; D036104:Receptor, EphA2
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