Protease-activated receptor 2 (PAR2) upregulates granulocyte colony stimulating factor (G-CSF) expression in breast cancer cells

Biochem Biophys Res Commun. 2018 Sep 26;504(1):270-276. doi: 10.1016/j.bbrc.2018.08.169. Epub 2018 Aug 30.


Protease-activated receptor 2 (PAR2) is a G-protein coupled receptor which is activated upon cleavage of its N-terminal region. PAR2 has been associated with many aspects regarding tumor progression, such as the production of pro-tumoral cytokines. Granulocyte colony-stimulating factor (G-CSF) is a cytokine essential to neutrophil production and maturation, and it is often overexpressed in tumors. In this study, we evaluated the ability of PAR2 to modulate G-CSF expression. PAR2 and G-CSF were significantly more expressed in metastatic (4T1 and MDA-MB-231) as compared to non-metastatic (67NR and MCF7) breast cancer cell lines. In addition, PAR2 stimulation by a synthetic agonist peptide significantly increased G-CSF gene expression in the metastatic cell lines. Knockdown of PAR2 in 4T1 cells decreased G-CSF expression and secretion. In addition, treatment of 4T1 with the commercial PAR2 antagonist, ENMD-1068, significantly decreased G-CSF expression. cBioPortal analyses of the TCGA database showed a significant co-occurrence of G-CSF and PAR2 gene overexpression in breast cancer samples. In conclusion, our data suggest that PAR2 contributes to G-CSF expression in breast cancer cells, possibly favoring tumor progression.

Keywords: Breast cancer; ENMD-1068; Granulocyte colony stimulating factor; Protease-activated receptor; TCGA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / metabolism*
  • Cell Line, Tumor
  • Cytokines / metabolism
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Granulocyte Colony-Stimulating Factor / metabolism*
  • HEK293 Cells
  • Humans
  • Mice
  • Receptor, PAR-2 / metabolism*
  • Receptors, G-Protein-Coupled / metabolism*
  • Transcriptional Activation
  • Up-Regulation


  • Cytokines
  • F2RL1 protein, human
  • F2rl1 protein, mouse
  • Receptor, PAR-2
  • Receptors, G-Protein-Coupled
  • Granulocyte Colony-Stimulating Factor