Proteinase-activated receptor 2 expression in breast cancer and its role in breast cancer cell migration

S. Su, Y. Li, Y. Luo, Y. Sheng, Y. Su, R. N. Padia, Z. K. Pan, Zheng Dong, Shuang Huang

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

Abstract

Proteinase-activated receptor 2 (PAR2) is a G protein-coupled receptor that is activated by trypsin-like proteinases. PAR2 is detected in breast tumor specimens; however, it is not clear how PAR2 level in breast cancer cell/tissues compares with normal cell/tissues. Here, we show the elevation of PAR2 protein level in 76 of 105 breast tumor specimens but only 5 of 24 normal breast tissues. PAR2 level is also higher in breast cancer cell lines than that in normal breast cells and non-cancerous breast cell lines. To determine the role of PAR2 in breast carcinogenesis, we examined the effect of PAR2 agonists on cell proliferation and migration. Our studies show that PAR2 agonists (PAR2-activating peptide and trypsin) are neither potent growth enhancers nor chemoattractants to breast cancer cells. Instead, PAR2 agonists induce significant chemokinesis. PAR2-mediated chemokinesis is Gαi- dependent, and inhibiting Src kinase activity or silencing c-Src expression blocks PAR2-mediated chemokinesis. These results suggest that c-Src works downstream of Gαi to mediate this PAR2 agonist-induced event. To characterize c-Src effector, we reveal that PAR2 agonists activate JNKs in a Src-dependent manner and that JNK activity is essential for PAR2-mediated chemokinesis. Moreover, PAR2 agonist stimulation leads to paxillin Ser 178 phosphorylation and paxillin(S178A) mutant inhibits PAR2-mediated chemokinesis. In conclusion, our studies show that PAR2 agonists facilitate breast cancer cell chemokinesis through the Gαi-c-Src-JNK- paxillin signaling pathway.

Original languageEnglish (US)
Pages (from-to)3047-3057
Number of pages11
JournalOncogene
Volume28
Issue number34
DOIs
StatePublished - Aug 27 2009

Keywords

  • Breast cancer
  • Chemokinesis
  • JNK
  • PAR2
  • Paxillin
  • Src

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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