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Purpose: Breast cancer (BC) brain metastasis (BrM) remains a significant clinical problem. Mucins have been implicated in metastasis; however, if they are also involved in BCBrM remains unknown. We queried BrM patient databases and found Mucin 5AC (MUC5AC) to be upregulated and therefore sought to define the role of MUC5AC in BCBrM., Experimental Design: In-silico dataset analysis, RNA-sequence profiling on patients and cell lines, analysis of patients' serum samples, and in-vitro/vivo knockdown experiments were performed to determine the function of MUC5AC in BCBrM. Coimmunoprecipitation unravels the interactions that can be therapeutically targeted., Results: Global in-silico transcriptomic analysis showed that MUC5AC is significantly higher in BCBrM patients. Archived BCBrM tissue analysis further revealed significantly higher expression of MUC5AC in all BC subtypes, and high MUC5AC expression predicted poor survival in HER2+ BCBrM. We validated these observations in BCBrM cell lines and tissue samples. Interestingly, elevated levels of MUC5AC were detected in the sera of BCBrM patients. MUC5AC silencing in BCBrM cells reduced migration, adhesion, and reduced BrM in experimental intracardiac injection mouse model. We found high expression of cMET and CD44v6 in BCBrM, which increased MUC5AC expression via HGF signaling. MUC5AC interacts with cMET and CD44v6, suggesting that MUC5AC promotes BCBrM via the cMET/CD44v6 axis. This axis can be targeted with c-MET inhibitor Bozitinib (PLB1001) to inhibit BCBrM., Conclusions: Our study establishes that the MUC5AC/cMET/CD44v6 axis is critical for BCBrM, and blocking this axis will be a novel therapeutic approach for BCBrM.