Regulation of thrombin-induced plasminogen activator inhibitor-1 in 4T1 murine breast cancer cells.

Protease-activated receptor-1 (PAR-1) and PAR-2 are overexpressed in cancer cells and activation of these receptors contributes to malignancy. We have recently shown that thrombin activates PAR-1, which induces transactivation of PAR-2, resulting in increased plasminogen activator inhibitor-1 (PAI-1) expression in 4T1 murine mammary adenocarcinoma cells. Our goal was to analyze the signal transduction pathways that regulate thrombin-induced PAI-1 expression. We found that thrombin stimulation activates the ERK1/2-ELK1-EGR1 pathway in 4T1 cells. Furthermore, inhibition of p42/p44 MAPK signaling reduced PAI-1 expression. These results begin to delineate the mechanism by which thrombin activates a PAR-1/PAR-2 complex to induce PAI-1 expression in the 4T1 murine breast cancer cell line.