Proteases give
cancer a defining characteristic of being able to break through extracellular matrix barriers and invade into other tissues in response to chemotactic signals. Recently, the cell surface
protease-activated receptor (PAR)-1 has been shown to act as a
chemokine receptor in inflammatory cells, and its expression is tightly correlated with metastatic propensity of
breast cancer cells. The aim of the present study was to determine whether activation of PAR1 or the other known PARs (PAR2-4) can regulate migration and invasion of
breast cancer cells. We found that the highly invasive MDAMB231
breast cancer cell line expressed very high levels of functional PAR1, PAR2, and PAR4, whereas minimally invasive MCF7 cells had trace amounts of PAR1 and low levels of PAR2 and PAR4. Despite the differences in expression, PAR2 and PAR4 acted as
chemokine receptors in both invasive and minimally invasive breast cell lines. Quite unexpectedly, we found that activation of PAR1 with
thrombin or the
peptide agonist
SFLLRN markedly inhibited invasion and migration of MDAMB231 cells when applied as a concentration gradient in the direction of cell movement. Additionally, we demonstrated that inhibition of chemotaxis was mediated through a G(i)/
phosphoinositide-3-
OH kinase-dependent pathway. Activation of G(i) signaling with
epinephrine or
wasp venom mastoparan also inhibited invasion and migration of the
breast cancer cells. These findings suggest that
therapeutics targeted toward G(i)-couplers that are selectively expressed in
breast cancer cells could prove beneficial in halting the progression of invasive
breast cancer.