The insulin-like growth factor-1 elevates urokinase-type plasminogen activator-1 in human breast cancer cells: a new avenue for breast cancer therapy.

Tumor recurrence is a common problem in the treatment of breast cancer. In breast cancer, the expression of high protein levels of the insulin-like growth factor-1 receptor (IGF-1R) and urokinase-type plasminogen activator-1 (uPA) is strongly associated with breast cancer recurrence and decreased survival. The expression of uPA by tumors is thought to not only stimulate tumor invasion but also facilitate angiogenesis. In this study, our goal was to address whether IGF-1R could influence the expression of the extracell ular matrix proteases, matrix metalloproteinase (MMP), or uPA thus allowing a selective advantage for tumor invasion and concomitant neovascularization. Initially, we determined whether or not insulin-like growth factor (IGF)-1 regulated the production MMP or uPA in the human breast cancer MDA-MB-231 cells. There was no increase in MMP activity when the cells were treated with IGF-1 (10 ng/mL) for 24 h. In contrast, uPA mRNA and protein were induced in a time-dependent manner. Furthermore, clones expressi ng a dominant negative inhibitor of IGF-1R termed 486stop had less uPA mRNA, and the clones were less invasive through Matrigel. Taken together, these data illustrate that IGF-1R stimulates uPA production. Hence, these two prognostic indicators may be interrelated, suggesting they may function in a synergistic manner to facilitate local tumor invasion as well as angiogenesis. Our data suggest that disruption of IGF-1 signaling in breast cancer may lead to breast cancer prevention and intervention by decreasing uPA expression. Copyright 2000 Wiley-Liss, Inc.