GLUT3 coordinates mitochondrial respiration and metabolic reprogramming in ERα-positive breast cancer

Breast cancer (BC) cells have enhanced glycolytic ability. The GLUT3 has a key effect on tumor development, but its non-classical function and associated mechanism in ERα-positive BC are largely unresolved. In this study, transcriptome and metabolomics were carried out for identifying molecular alterations in GLUT3-overexpressing T47D cells, which revealed that pathways related to signal transduction (FoxO, cAMP, and PI3K-Akt-mTOR signaling pathways), energy metabolism, central carbon metabolism in cancer, and lipid metabolism were preferentially enriched. Further correlation analysis suggested that major DEMs and DEGs were involved in pathways associated with glycometabolism, lipid metabolism, oxidation reactions, and energy metabolism. Then, the Co-IP/MS and UPLC-MS analysis results showed that GLUT3 may be one of the key cellular factors for energy metabolism-related aerobic respiration, oxidative phosphorylation, and oxidation- reduction reactions. Specifically, the GLUT3 may enhance the oxidative phosphorylation efficiency of BC cells via physical interaction with the aerobic respiratory-related complex, upregulation of complex I and V enzyme activity, and the production of acetyl-CoA, succinyl-CoA, and other TCA intermediates. This finding challenges the generality of the traditional Warburg effect in BC, suggesting that GLUT3 may support the proliferation of tumor cells through a dual metabolic pattern of glycolysis and oxidative phosphorylation.