Abstract
BACKGROUND: HER2-positive breast cancer is an aggressive subtype where innate/acquired resistance to targeted drugs remains a challenge. This study aims to uncover the underlying mechanisms of HER2 drug resistance through miRNA analysis and target identification. METHODS: MiRNA datasets were systematically retrieved from the GEO database, and differential expression analysis was conducted for both miRNA and mRNA datasets. Functional analyses were also conducted to validate the identified miRNAs and assess their clinical relevance. RESULTS: We identified 113 differentially expressed miRNAs (DEMs) and 923 target genes. Validation was performed using external mRNA datasets, and intersection with significant genes identified 110 overlapping genes associated with HER2 drug resistance. Further analyses included functional enrichment, construction of a protein-protein interaction (PPI) network, identification of key hub genes such as BCL2, FOS, and CXCR4, and assessment of clinical relevance through survival analysis and immunohistochemistry (IHC) assessments. CONCLUSIONS: This integrative approach unveils a complex landscape of HER2 drug resistance in breast cancer, identifying crucial miRNAs, target genes, and significant pathways. The findings offer novel insights into the mechanisms governing drug resistance and highlight the potential for enhancing therapeutic strategies. Future studies are necessary for experimental validation to further explore the complex mechanisms involved.