Breast cancer metastasis to the brain: Genetic determinants and mediators of passage through the blood-brain barrier

Brain metastasis is the most common malignancy of the central nervous system. It affects 20-30% of breast cancer patients with disseminated disease, occurring years after primary cancer diagnosis. This latency period suggests that tumor cells must acquire specific functions for brain dissemination. Improvements in systemic therapy that prolong survival, as well as a lack of knowledge about this process contribute to its rising incidence. We have isolated cell populations from breast cancer pleural effusions that preferentially metastasize to the brain in mice. Inspection of their transcriptomic profiles, coupled with bioinformatics analysis of gene expression data from human breast tumors, revealed a set of genes associated with brain metastatic relapse in breast cancer patients. Functional analysis performed in the mouse and in vitro identified the cyclooxygenase COX2, the EGFR ligand HB-EGF and the alpha2-6 sialyltransferase ST6GalNac5 as mediators of cancer cell passage through the blood-brain barrier. COX2 and EGFR ligands were previously linked to breast cancer cell infiltration of the lungs but not the bones or liver, suggesting a partial sharing of mediators of brain and lung metastases. In contrast, ST6GalNac5 specifically mediates brain metastasis, but not metastasis to the lungs. Normally restricted to the brain, the expression of ST6GalNac5 in breast cancer cells enhances their adhesion to brain microvascular endothelia and their passage through the blood-brain barrier. We suggest that breast cancer metastasis to brain involves shared mediators of trans-endothelial migration reinforced by specific enhancers of blood-brain barrier crossing and brain colonization. The co-option of a brain sialyltransferase for brain metastasis highlights the role of cell-surface glycosylation in organ-specific metastatic processes.