The role of NETosis in breast cancer: mechanistic insights and biomarker potential

Neutrophil extracellular trap formation (NETosis), previously described as an effector host defense mechanism, is more frequently associated with cancer-driven inflammation and tumor development. In the case of breast cancer, NETosis assists with several oncogenic processes, including epithelial-mesenchymal transition, immune evasion, organotropic metastasis, angiogenesis, and resistance to therapy. The current study summarizes the evidence of the mechanistic role of NETs in breast cancer and their potential to act as a diagnostic, prognostic, or therapeutic biomarker. Like many other promising candidates for novel prognostic or diagnostic biomarkers, citrullinated histone H3 (citH3), myeloperoxidase-DNA (MPO-DNA) complexes, and circulating cell-free DNA (cfDNA) need further validation to be functional. However, there is some evidence suggesting clinical relevance. Like many candidate therapeutic indices, several therapies are exploring targeting NETosis, including deoxyribonuclease I (DNase I) and peptidyl arginine deiminase 4 (PAD4) inhibitors, as a clinical intervention. However, methodological differences across studies and a lack of standardized detection of NETs are likely impeding future findings. Future insight into the efficiency of detection methods and consistency of experimental design will be beneficial for transferring NETosis to the clinic.