Abstract 1251: Increased expression of the plasminogen activator system due to differential protease-activated receptor signaling in breast cancer cells

Abstract

Abstract Activation of protease activated receptor-1 and −2 (PAR-1 and PAR-2) on tumor cells by coagulation proteases, such as factor Xa (FXa) and thrombin, leads to the expression of urokinase plasminogen activator (uPA) and its inhibitor plasminogen activator inhibitor type-1 (PAI-1). uPA has been shown to contribute to malignancy by increasing tumor cell migration, survival, extracellular matrix degradation, and angiogenesis. The goal of this study was to determine how activation of PAR-1 and PAR-2 by coagulation proteases regulates uPA and PAI-1 expression. We used the 4T1 mouse mammary adenocarcinoma cell line as a model because it expresses both PAR-1 and PAR-2. Using shRNA technology, we made derivatives of the 4T1 cells with reduced expression of either PAR-1 or PAR-2. 4T1 cells carrying a non-targeting shRNA construct were used as negative controls. We found that FXa and thrombin induced uPA expression in the control and the PAR-2 shRNA cells, but not in the PAR-1 shRNA cells. In contrast, FXa treatment did not increase PAI-1 levels in the control, PAR-1 shRNA, or PAR-2 shRNA cells. Thrombin was able to induce PAI-1 in the control cells, but not in the PAR-1 shRNA or the PAR-2 shRNA cells. Taken together, our data suggests that uPA expression is dependent on PAR-1 activation whereas PAI-1 expression requires a PAR-1/PAR-2 heterodimer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1251.