Unveiling Novel Molecular Drivers in Breast Cancer Brain Metastasis: Multi-Omics Integration Identifies Downregulation of VCAN and Emerging Roles of ASCL2/GRAMD1A as Prognostic Biomarkers and Therapeutic Vulnerabilities

Purpose Breast cancer brain metastasis (BCBM) presents a major clinical challenge, driven by molecular mechanisms that remain poorly characterized. Patients and methods Three RNA-seq datasets (GSE110590, GSE193103, GSE209998) were analyzed to identify BCBM-associated genes. Survival outcomes (2,976 primary tumors) were assessed via Kaplan-Meier (KM Plotter), genetic alterations via cBioPortal, pathways/networks via GeneMANIA/SIGNOR, and miRNA-mRNA interactions via miRNet. Drug candidates were prioritized using the CTD. Results TNFRSF9 and VCAN were downregulated (log2FC: −1.18 to −2.63), while GRAMD1A, ASCL2, TACC3, and PFKFB4 were upregulated (log2FC: +1.02 to +1.70). High PFKFB4 (HR=1.71) and TACC3 (HR=1.46) predicted poor survival, with VCAN suppression (Fold change (Fc) =0.24) and GRAMD1A elevation (Fc=1.31) confirmed in metastases. Pathways included ECM remodeling (VCAN), metabolic rewiring (PFKFB4), and mitotic instability (TACC3). miR-210-3p (hypoxia) and miR-27a-3p (angiogenesis) drove BCBM, countered by miR-335/34a. Drug candidates: Valproic Acid (TACC3/ASCL2), Vorinostat (VCAN), and CDK4/6 inhibitors. Conclusion This study identifies TNFRSF9, VCAN, GRAMD1A, ASCL2, TACC3, and PFKFB4 as key drivers of BCBM, with dysregulation linked to immune evasion, metabolic adaptation, and mitotic instability. Prioritized miRNAs (e.g., miR-210-3p) and repurposed drugs (e.g., Valproic Acid, Vorinostat) offer actionable therapeutic strategies. These findings advance precision approaches for BCBM, pending preclinical validation to translate targets into clinical practice.