| Abstract: |
In search of redox mechanisms in breast cancer, we uncovered a striking role for glutathione peroxidase 2 (GPx2) in oncogenic signaling and patient survival. GPx2 loss stimulates malignant progression due to reactive oxygen species/hypoxia inducible factor-α (HIF1α)/VEGFA (vascular endothelial growth factor A) signaling, causing poor perfusion and hypoxia, which were reversed by GPx2 reexpression or HIF1α inhibition. Ingenuity Pathway Analysis revealed a link between GPx2 loss, tumor angiogenesis, metabolic modulation, and HIF1α signaling. Single-cell RNA analysis and bioenergetic profiling revealed that GPx2 loss stimulated the Warburg effect in most tumor cell subpopulations, except for one cluster, which was capable of oxidative phosphorylation and glycolysis, as confirmed by coexpression of phosphorylated-AMPK and GLUT1. These findings underscore a unique role for redox signaling by GPx2 dysregulation in breast cancer, underlying tumor heterogeneity, leading to metabolic plasticity and malignant progression. © 2022 National Academy of Sciences. All rights reserved. |
| Keywords: |
signal transduction; vascular endothelial growth factor a; genetics; mouse; animal; metabolism; animals; mice; breast cancer; drug screening; xenograft model antitumor assays; cell line, tumor; breast neoplasms; neovascularization, pathologic; physiology; nude mouse; mice, nude; breast tumor; tumor cell line; vasculotropin a; reactive oxygen species; reactive oxygen metabolite; hypoxia inducible factor 1alpha; neovascularization (pathology); glycolysis; oxidative phosphorylation; oxidation reduction reaction; oxidation-reduction; hif1a protein, human; hypoxia-inducible factor 1, alpha subunit; vegfa protein, human; cell plasticity; glutathione peroxidase; humans; human; female; glutathione peroxidase 2; hif1α; ros signaling; gpx2 protein, human
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