Onconeural antigen NOVA1 dysregulates RNA alternative splicing in breast cancer

The neuron-specific splicing factor NOVA1 was first discovered as an onconeural antigen ectopically expressed in breast tumors, causing rare autoimmune reactions and paraneoplastic neurological disorders (PNDs). The PND model suggests a plausible role of the tumor antigen expression in tumor suppression, whereas it has emerged that NOVA exhibits oncogenic activity in cell-based models. Whether NOVA mediates alternative splicing (AS) in native cancer remains unknown. Here we examine the AS profiles of breast invasive carcinoma (BRCA) tumor samples and demonstrate that aberrant NOVA1 overexpression led to the activation of neuron-like splicing patterns in many genes, including alternative exons targeted by NOVA in the brain. The splicing dysregulation is especially prevalent in cell periphery and cytoskeleton genes related to cell-cell communication, actin-based movement, and neuronal functions. We find that NOVA1-mediated AS is most prominent in Luminal A tumors and high NOVA1 expression in this subtype is associated with poorer prognosis. Our results suggest that ectopic NOVA1 in tumors has regulatory activity affecting pathways with high relevance to tumor progression.