The hexosamine biosynthesis pathway as a potent culprit in breast cancer progression

The hexosamine biosynthesis pathway (HBP) is a nutrient-sensitive branch of glucose metabolism that produces UDP-GlcNAc, a central substrate for protein glycosylation. Growing evidence links altered HBP activity to breast cancer (BC) progression and treatment response. However, the strength of evidence differs across tumor subtypes and across experimental versus patient data. This review summarizes current clinical and preclinical evidence on how HBP enzymes and HBP-derived glycosylation contribute to BC biology. Across BC cohorts and experimental models, increased expression of key HBP components has been associated with aggressive features, while mechanistic studies show that HBP activity can support oncogenic signaling through elevated O-GlcNAcylation of regulatory proteins. Work in BC models further indicates that HBP-related changes influence proliferation, survival, epithelial-mesenchymal transition, migration, and invasion, and may interact with pathways such as PI3K/AKT/mTOR, Wnt/β-catenin, and YAP. Evidence discussed in this review also links HBP output to stress-adaptation programs, including DNA damage responses and ER protein-folding capacity via N-linked glycosylation, which can promote survival under nutrient or therapy stress. Therapeutic studies described here include direct and indirect strategies to reduce HBP output, such as targeting pathway enzymes, modulating O-GlcNAc cycling, and using hexosamine analogs designed to disrupt flux or glycan function; these approaches reduce growth and metastatic behavior in several preclinical settings, but specificity and normal-tissue tolerance remain key constraints. Overall, the literature supports HBP as a plausible metabolic contributor to BC progression, but stronger patient-linked validation is needed. Future work should prioritize subtype-resolved clinical studies and direct measures of pathway activity to guide biomarker development and therapeutic targeting.