This study examines the critical role of DNA topoisomerase II alpha (TOP2A) phosphorylation in breast cancer progression, regulated by the SRY-box transcription factor 4 (SOX4)/Casein kinase II subunit alpha 1 (CSNK2A1) axis. Using integrated transcriptomic and proteomic analyses, data were sourced from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) and The Cancer Genome Atlas (TCGA) databases. To explore the dataset, differential analysis, kinase-substrate enrichment analysis (KSEA), and weighted gene co-expression network analysis (WGCNA) were performed. Immune profiling, combined with survival analysis, revealed the prognosis linked to different immune profiles in breast cancer patients. In vitro experiments assessed the effect of SOX4 on CSNK2A1 promoter activity through real-time quantitative polymerase chain reaction (RT-qPCR), Western blot, dual-luciferase reporter assays, and chromatin immunoprecipitation (ChIP). The phosphorylation level of TOP2A was also measured. Cell proliferation, migration, and invasion were evaluated using cell counting kit-8 (CCK-8), colony formation, and Transwell assays. In vivo studies extended to mouse models, where the effect of SOX4 on CSNK2A1-TOP2A phosphorylation was analyzed about tumor growth and metastasis. The results showed that upregulation of SOX4 increases CSNK2A1 transcription, which in turn promotes TOP2A phosphorylation and accelerates breast cancer progression. The clinical analysis identified three immune profiles, with the intermediate profile associated with a poorer prognosis, possibly due to enhanced TOP2A phosphorylation mediated by SOX4/CSNK2A1. Silencing SOX4 significantly reduced cell proliferation, migration, invasion, and tumor growth in vivo by lowering CSNK2A1-TOP2A phosphorylation. These findings highlight the therapeutic potential of targeting the SOX4/CSNK2A1 axis in breast cancer and provide insight into its mechanism through TOP2A phosphorylation.