Abstract：
Neutrophil and neutrophil extracellular traps (NETs) were reported to be associated with tumor development, but the exact role and concrete mechanisms are still poorly understood, especially in triple negative breast cancer (TNBC). In this study, our results exhibited that NETs formation in TNBC tissues was higher than that in non-TNBC tissues, and NETs formation was distinctly correlated with tumor size, ki67 level and lymph node metastasis in TNBC patients. Subsequent in vivo experiments demonstrated that NETs inhibition could suppress TNBC tumor growth and lung metastasis. Further in vitro experiments uncovered that oncogenic function of NETs on TNBC cells were possibly dependent on TLR9 expression. We also found that neutrophils from peripheral blood of TNBC patients with postoperative fever were prone to form NETs and could enhance the proliferation and invasion of TNBC cells. Mechanistically, we revealed that NETs could interact with TLR9 to decrease Merlin phosphorylation which contributed to TNBC cell ferroptosis resistance. Our work provides a novel insight into the mechanism of NETs promoting TNBC progression and blocking the key modulator of NETs might be a promising therapeutic strategy in TNBC.
摘要：
据报道，中性粒细胞和中性粒细胞胞外诱捕网(NETs)与肿瘤的发展有关，但是确切的作用和具体的机制仍然知之甚少，尤其是三阴性乳腺癌（TNBC）。在这项研究中,我们的结果表明，在TNBC组织中的NETs形成高于非TNBC组织，NETs的形成与肿瘤大小明显相关，TNBC患者的ki67水平和淋巴结转移。随后的体内实验表明，抑制NETs可以抑制TNBC肿瘤的生长和肺转移。进一步的体外实验发现，NETs对TNBC细胞的致癌功能可能取决于TLR9的表达。我们还发现，术后发热的TNBC患者外周血中性粒细胞易形成NETs，并可增强TNBC细胞的增殖和侵袭能力。机械上,我们发现，NETs可以与TLR9相互作用以减少Merlin磷酸化，这有助于TNBC细胞铁凋亡抗性。我们的工作为NETs促进TNBC进展和阻断NETs关键调节剂的机制提供了新的见解，这可能是TNBC的有前途的治疗策略。
