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

Abstract

Proteinase-activated receptor 2 (PAR2) is a G proteincoupled 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 G ai -dependent, and inhibiting Src kinase activity or silencing c-Src expression blocks PAR2-mediated chemokinesis. These results suggest that c-Src works downstream of G ai 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 G ai -c-Src-JNKpaxillin signaling pathway.

Gene expression profiling identifies sST2 as an effector of ErbB2-driven breast carcinoma cell motility, associated with metastasis

“…However, among the genes we tested, only F2RL1/PAR2 and sST2 contributed to ErbB2-driven migration. PAR2 activation promotes breast cancer cell migration (Morris et al, 2006;Su et al, 2009). Interestingly, this function could be mediated by transactivation of EGFR/ErbB2 (Caruso et al, 2006;Jarry et al, 2007), suggesting the possibility of a positive feedback loop.…”

“…Depletion of IL1RL1/ST2 or F2RL1 strongly reduced HRG-induced migration of both T47D and SKBr3 cells (Figure 3a). The F2RL1 gene encodes the protease-activated receptor-2 (PAR2) protein, whose role in migration of breast cancer cells is documented (Su et al, 2009). The IL1RL1/ST2 protein, which belongs to the IL-1R gene family, is an effector of T-helper 2 responses (Meisel et al, 2001;Schmitz et al, 2005;Kakkar and Lee, 2008), but widespread expression of variant 2 suggests a role in different cellular functions.…”

MLK3 is critical for breast cancer cell migration and promotes a malignant phenotype in mammary epithelial cells

“…However, our findings that an MLK inhibitor can block the migration of invasive breast cancer cells and that JNK inhibition blocks MLK3-induced migration in MCF-7 and MCF10A cells supports the idea that, at least in the context of breast cancer, MLK3-JNK signaling is crucial for cell migration. Indeed, a significant body of literature indicates a requirement for JNK in cancer progression (Cui et al, 2006;Ching et al, 2007;Dhillon et al, 2007;Khatlani et al, 2007;Vivanco et al, 2007;Su et al, 2009;Wagner and Nebreda, 2009).…”

Differential roles of Src in transforming growth factor-ß regulation of growth arrest, epithelial-to-mesenchymal transition and cell migration in pancreatic ductal adenocarcinoma cells

“…Src together with · V ß3 integrin promotes anchorage-independent growth and metastasis (2) and recent data have revealed that transient activation of Src by immortalized mammary epithelial cells triggered an inflammatory response that resulted in the initiation and maintenance of cellular transformation and a switch from a non-transformed to a transformed phenotype (3). Src mediates signaling from many types of receptors including receptor tyrosine kinases (EGF-R), integrins, and G-protein-coupled receptors such as proteinase-activated receptors (PARs) (4). Src is required for EGF-R stimulated DNA synthesis and has been reported to stimulate IGF-I-dependent cell proliferation by increasing IGF-I receptor number (5).…”