P06.10 Targeting GALE-mediated nucleotide sugar homeostasis suppresses breast cancer cell invasive behavior

Background Breast cancer progression requires coordinated regulation of glycosylation and cellular metabolism, yet the molecular mechanisms integrating these processes to drive aggressive disease remain poorly defined. UDP-galactose 4-epimerase (GALE), which interconverts UDP-galactose/UDP-GalNAc and UDP-glucose/UDP-GlcNAc, represents a central node controlling nucleotide-sugar homeostasis that is essential for both glycosylation and cellular metabolism.Material and methods Public breast cancer transcriptomic datasets were analyzed to assess GALE expression, patient survival, and immune cell infiltration across molecular subtypes. GALE function was examined using genetic depletion in breast cancer cell lines followed by migration and invasion assays, together with Seahorse analyses of glycolytic activity and mitochondrial respiration. GALE-dependent glycosylation remodeling was characterized by examining Golgi-mediated glycosylation and intracellular protein O-GlcNAcylation. Molecular docking was performed to identify candidate GALE-binding compounds.Results GALE was significantly upregulated in breast tumors, and high GALE expression was associated with poor overall survival in both triple-negative and ER +/PR+/HER2− subtypes. Genetic depletion of GALE markedly suppressed breast cancer cell migration and invasion and impaired both glycolytic activity and mitochondrial respiration, indicating an essential role in maintaining metabolic fitness. Mechanistically, GALE depletion reduced UDP-GlcNAc availability, leading to global suppression of protein O-GlcNAcylation, while concomitantly increasing UDP-galactose levels and inducing Golgi-mediated glycosylation remodeling characterized by enhanced terminal β-galactosylation and LacNAc extension. Immune profiling revealed subtype-specific associations: in triple-negative breast cancer, high GALE expression was associated with reduced cytotoxic CD8+ T-cell infiltration, consistent with an immune-excluded phenotype; in contrast, in ER+/PR+/HER2− breast cancer, GALE expression correlated with Th1-related immune signaling without increased CD8+ T-cell infiltration, indicative of an immune-quiescent microenvironment. Structure-based molecular docking identified multiple clinically relevant compounds with predicted GALE-binding activity.Conclusions GALE acts as a central nucleotide-sugar homeostasis regulator that coordinates glycan remodeling, metabolic adaptation, and immune contexture in breast cancer. These findings establish GALE as a druggable glyco-metabolic node whose inhibition may suppress breast cancer invasiveness and modulate immune exclusion, supporting GALE as a promising therapeutic target.