Alternative splicing rewires breast cancer and opens therapeutic avenues

Breast cancer exhibits profound molecular and clinical heterogeneity, manifested through diverse subtypes, metastatic patterns, and therapeutic responses. Emerging evidence underscores that this complexity stems not merely from genetic and epigenetic aberrations but also from post-transcriptional regulatory mechanisms, particularly alternative splicing (AS), which amplifies proteomic diversity and functional versatility. AS generates multiple mRNA isoforms from a single gene, directly influencing oncogenic processes including cell migration, metabolic reprogramming, immune evasion, and therapy resistance. Recent advances in high-throughput sequencing and bioinformatics have enabled systematic mapping of AS landscapes in breast cancer. This review delineates the mechanistic underpinnings of AS regulation and synthesizes cutting-edge discoveries in AS-driven oncogenic pathways. We further evaluate the translational potential of AS signatures in clinical applications, such as molecular subtyping, prognostic biomarkers, and splice-switching therapeutics. Finally, we address persisting challenges, including tumor heterogeneity and the lack of splicing specificity, that must be overcome to harness AS modulation as a precision oncology strategy.