Abstract Background: Tumor heterogeneity fuels breast cancer metastasis by selecting subpopulations withepithelial-mesenchymal (EMT) plasticity and stemness. Loss of the antioxidant enzyme glutathione peroxidase 2 (GPx2) in the PyMT mouse model promotes phenotypic and metabolic reprogramming through ΔNp63-regulated hybrid EMT and fatty acidoxidation (FAO)-driven metabolism. Results: Using our newly engineered PyMT/GPx2 knockout (KO) transgenic mouse model, we observed a striking increase in reactive oxygen species (ROS), HIF1α stabilization, vascular malformation, proliferation (Ki67), stemness (organoid formation), and lung metastasis compared with control tumors. GPx2-deficient tumors were markedly enrichedfor hybrid EMT cells co-expressing p63, KRT8, and KRT14. Flow cytometry confirmed that ∼85% of GPx2-KO tumor cells were hybrid (CD104+/CD44+), with only minor epithelial (CD104+/CD44-, ∼4%) and mesenchymal (CD104-/CD44+, ∼0.8%) fractions. Metabolic profiling revealed FAO as the dominant energy source in GPx2-KO tumors, supported by Seahorse assays showing elevated mitochondrial ATP production, a higherOCR/ECAR ratio, and enhanced palmitate oxidation. GPx2 loss increased p-AMPK,indicative of AMPK-mediated OXPHOS activation, and upregulated GLUT1 whilesuppressing de novo lipogenesis. These changes indicate dependence on exogenousfatty acids through CD36/CPT1-mediated β-oxidation. Notably, lung metastases derivedfrom GPx2-KO tumors showed a shift toward glycolytic metabolism, highlightingmetabolic plasticity during dissemination. Conclusion: GPx2 loss integrates redox dysregulation with EMT and metabolic reprogramming, fostering hybrid E/M cells endowed with high metastatic potential and adaptive energymetabolism. Clinical implications: Targeting ΔNp63 signaling or FAO pathways may selectively eliminate metabolically flexible, aggressive hybrid tumor populations, offering a potential strategy to mitigate breast cancer metastasis. Citation Format: Rachel Hazan, Viney Kumar, Outhiriaradjou Benard, Larry premprashant chaudhary, mahaldeep kaur, Ian, Bethesda, Norton. Redox regulation of breast cancer metastasis via phenotypic and metabolic adaptation abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 848.
Hazan et al. (Fri,) studied this question.