C-FOS promotes the formation of neutrophil extracellular traps and the recruitment of neutrophils in lung metastasis of triple-negative breast cancer.

BACKGROUND: Neutrophil extracellular traps (NETs) are composed of DNA chains from neutrophils and associated proteolytic enzymes, which play an important role in cancer metastasis. However, the molecular mechanism of NET-mediated lung metastasis in triple-negative breast cancer (TNBC) remains unclear. METHODS: The expression levels of NETs in breast cancer specimens and serum were analyzed and compared with normal samples. Single-cell sequencing bioinformatics analysis was conducted to identify differentially expressed genes and functional enrichment related to NET formation in patients with breast cancer. The effects of c-FOS on neutrophil recruitment and NET formation in TNBC were investigated. The upstream and downstream regulatory mechanisms mediated by c-FOS were explored through in vitro and in vivo experiments. Therapeutic approaches targeting c-FOS for treating TNBC were further studied. RESULTS: Inhibition of c-FOS can suppress tumor growth and lung metastasis in TNBC. Mechanistically, c-FOS promotes transcription by binding to the PAD4 promoter region, facilitating the formation of NETs. Additionally, the activation of the ROS-p38 pathway further enhances c-FOS expression. High expression of c-FOS also promotes the expression of inflammatory factors, facilitating neutrophil recruitment. Both in vitro and in vivo experiments demonstrated that the application of T5224 effectively inhibits the formation of NETs, suppressing lung metastasis and tumor growth. CONCLUSION: In summary, this study demonstrates that the ROS-p38-cFOS-PAD4 axis can increase NET formation in TNBC and promote the expression of inflammatory factors, facilitating neutrophil recruitment. Therefore, targeting this pathway may help inform new therapeutic strategies and provide new insights for immunotherapy in TNBC.