Nicotine promotes breast cancer metastasis by stimulating N2 neutrophils and generating pre-metastatic niche in lung

Nat Commun. 2021 Jan 20;12(1):474. doi: 10.1038/s41467-020-20733-9.


Smoking has a profound impact on tumor immunity, and nicotine, which is the major addictive component of smoke, is known to promote tumor progression despite being a non-carcinogen. In this study, we demonstrate that chronic exposure of nicotine plays a critical role in the formation of pre-metastatic niche within the lungs by recruiting pro-tumor N2-neutrophils. This pre-metastatic niche promotes the release of STAT3-activated lipocalin 2 (LCN2), a secretory glycoprotein from the N2-neutrophils, and induces mesenchymal-epithelial transition of tumor cells thereby facilitating colonization and metastatic outgrowth. Elevated levels of serum and urine LCN2 is elevated in early-stage breast cancer patients and cancer-free females with smoking history, suggesting that LCN2 serve as a promising prognostic biomarker for predicting increased risk of metastatic disease in female smoker(s). Moreover, natural compound, salidroside effectively abrogates nicotine-induced neutrophil polarization and consequently reduced lung metastasis of hormone receptor-negative breast cancer cells. Our findings suggest a pro-metastatic role of nicotine-induced N2-neutrophils for cancer cell colonization in the lungs and illuminate the therapeutic use of salidroside to enhance the anti-tumor activity of neutrophils in breast cancer patients.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Biomarkers, Tumor
  • Breast Neoplasms / chemically induced*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lipocalin-2 / metabolism
  • Lung / metabolism*
  • Lung / pathology
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • Mice
  • Neoplasm Metastasis* / genetics
  • Neutrophil Infiltration / drug effects
  • Neutrophils / metabolism*
  • Nicotine / adverse effects*
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • Smoking


  • Biomarkers, Tumor
  • LCN2 protein, human
  • Lipocalin-2
  • STAT3 Transcription Factor
  • Nicotine