NF-κB and neutrophil extracellular traps cooperate to promote breast cancer progression and metastasis

Aberrant NF-kappa B activation and neutrophil extracellular traps (NETs) are associated with breast cancer progression. How NF-kappa B and NETs modulate each other in breast cancer development remains unclear. Here, we found that NETs induced by phorbol 12-myristate 13-acetate promote breast cancer cell progression. In turn, cancer cells-derived factors, such as IL-8 and granulocyte colony-stimulating factor, stimulate neutrophils to form NETs. Mechanistically, NETs increased the interaction of NF-kappa B essential modifier (NEMO) with I kappa B kinase (IKK)alpha/beta and enhanced NF-kappa B activation. We then employed a cell-permeable peptide corresponding to the NEMO-binding domain (NBD) of IKK alpha/beta, termed NBD peptide, which disrupts NETs-mediated NEMO interaction with IKK alpha/beta and abolished NF-kappa B activation in vitro. NBD peptide also reduced IL-8 level and NETs formation, and suppressed primary tumor growth and/or lung metastasis in human breast cancer mouse xenograft models and mouse spontaneous breast cancer model. Blockade of NET formation using a peptidylarginine deiminase 4 (PAD4) pharmacologic inhibitor decreased NF-kappa B activation and tumor metastasis. Collectively, these data suggest that NF-kappa B associates with NETs to form a positive loop facilitating breast tumor progression and metastasis, and that selective inhibition of NF-kappa B and PAD4-dependent NETs provides an effective therapeutic approach for treating breast cancer.

Automated summary

Aberrant activation of NF-kappa B and formation of neutrophil extracellular traps (NETs) are associated with breast cancer progression. This study shows that there is a positive feedback loop between NF-kappa B and NETs, facilitating breast tumor progression and metastasis. Inhibition of NET formation or NF-kappa B activation may offer an effective therapeutic approach for treating breast cancer.