DNM1L as a prognostic biomarker and therapeutic target in breast cancer: A multi-omics analysis and In vitro validation

Abstract Background: Breast cancer is the most commonly diagnosed cancer and the leading cause of tumor-related death in women. Although the role of the Dynamin 1-like ( DNM1L ) gene in mitochondrial dynamics is well established, its clinical relevance and molecular mechanisms in breast cancer remain unclear. Objectives: This study employed a multi-omics approach to investigate the prognostic significance of DNM1L , its underlying mechanisms, and potential therapeutic strategies. Methods: This was a retrospective, multi-omics bioinformatics study integrating genomic, transcriptomic, and pharmacogenomic datasets to investigate the role of DNM1L in breast cancer. RNA sequencing and clinical data from TCGA-BRCA were analyzed alongside pharmacogenomic profiles from the Q-omics platform. Genetic alterations were examined using cBioPortal, DriverDBv4, and TIMER2.0, while differential expression and prognostic significance were assessed with UALCAN, CAMOIP, KM Plotter, and Q-omics. Tumor microenvironment profiling was conducted using the Tumor-Immune System Interaction Database. Functional validation was performed through CRISPR-based loss-of-function screening in breast cancer cell lines to evaluate gene networks and drug sensitivity, with a focus on the therapeutic potential of combining DNM1L targeting with pazopanib treatment. Results: DNM1L gene alterations were not associated with mutation frequency; however, elevated DNM1L mRNA levels were linked to BRCA1 hypermethylation, a marker of poor prognosis. DNM1L expression positively correlated with copy number variation and was significantly higher in tumor tissues compared to normal tissues. High DNM1L expression was associated with reduced overall survival and an immunosuppressive tumor microenvironment. CRISPR-mediated in vitro screening confirmed the involvement of DNM1L in cell cycle regulation and revealed heightened sensitivity to pazopanib in DNM1L knockout models. Conclusion: DNM1L is a potential prognostic biomarker in breast cancer, with high expression linked to poor survival outcomes. Targeting DNM1L in combination with pazopanib may offer a promising precision medicine strategy.