Obesity and Breast Cancer: The Roles of Peroxisome Proliferator-Activated Receptor-𝛾 and Plasminogen Activator Inhibitor-1

Figure 1

Plasminogen Activator System at the Tumor Cell Surface. Besides its traditional role as a protease inhibitor, the multiple roles of PAI-1 including cell de-adhesion, proliferation/apoptosis, and cell signaling suggest that PAI-1 expression in the tumor microenvironment enhances tumor cell progression. (Left panel) The catalytic activity of urokinase (uPA) is enhanced when bound to the cell surface by uPAR. uPA cleaves the zymogen plasminogen to its active form, the serine protease plasmin. Plasmin can subsequently activate matrix metalloproteases (MMP’s) in the extracellular matrix (ECM) microenvironment. Thus, the uPA/uPAR complex and MMP activation contribute to tumor cell invasion and metastasis by degradation of ECM components. (Middle panel) PAI-1 directly inhibits the active site of uPA whether it is free or bound to uPAR, and reduces further activation of plasminogen to plasmin. The PAI-1 paradox exists because this inhibition reaction should reduce tumor cell progression and invasion. (Right panel) When uPA is neutralized by PAI-1, the trimeric PAI-1/uPA/uPAR complex is recognized by the lipoprotein related protein (LRP) and internalized. Furthermore, PAI-1 has vitronectin (VN) binding sites and causes tumor cell detachment away from the ECM. This figure is based on a schematic from [13].