The study investigates the molecular mechanisms underlying breast cancer metastasis to the brain. It identifies COX2 (cyclooxygenase-2), HBEGF (heparin-binding epidermal growth factor), and ST6GALNAC5 (α2,6-sialyltransferase) as key mediators of this process. COX2 and EGFR ligands enhance cancer cell extravasation through non-fenestrated capillaries, while ST6GALNAC5 specifically facilitates passage through the blood-brain barrier (BBB). These findings highlight the role of cell-surface glycosylation in organ-specific metastatic interactions and suggest potential therapeutic targets for disrupting these processes. The study also reveals that brain metastasis is a late event in breast cancer, often occurring years after the initial tumor removal, and that the expression of ST6GALNAC5 in breast cancer cells enhances their adhesion to brain endothelial cells and their ability to pass through the BBB.The study investigates the molecular mechanisms underlying breast cancer metastasis to the brain. It identifies COX2 (cyclooxygenase-2), HBEGF (heparin-binding epidermal growth factor), and ST6GALNAC5 (α2,6-sialyltransferase) as key mediators of this process. COX2 and EGFR ligands enhance cancer cell extravasation through non-fenestrated capillaries, while ST6GALNAC5 specifically facilitates passage through the blood-brain barrier (BBB). These findings highlight the role of cell-surface glycosylation in organ-specific metastatic interactions and suggest potential therapeutic targets for disrupting these processes. The study also reveals that brain metastasis is a late event in breast cancer, often occurring years after the initial tumor removal, and that the expression of ST6GALNAC5 in breast cancer cells enhances their adhesion to brain endothelial cells and their ability to pass through the BBB.