Insulin-like growth factor 1 (ICF-1) and urokinase-type plasminogen activator (uPA) are inversely related in human breast fibroblasts

Human breast fibroblasts have been shown to express urokinase-type plasmino gen activator (uPA). This suggests that fibroblasts are actively involved i n the process of uPA-directed breast tumor proteolysis. To investigate a po ssible role for the insulin-like growth factors (IGFs) in regulating uPA ex pression in human breast fibroblasts? we correlated the expression of uPA w ith the expression of IGF-1 and IGF-2 in a paired panel of normal and tumor tissue-derived human breast fibroblasts in vitro. Analysis of reverse tran scribed polymerase chain reaction (RT-PCR) amplified mRNA revealed that the tumor-derived fibroblast strain expressed significantly more basal uPA mRN A and significantly less IGF-1 mRNA when compared to their normal counterpa rt. The expression of basal IGF-2 mRNA did not differ between these culture s. For both normal and tumor tissue-derived fibroblasts, cytokine- and grow th factor-induced steady-state levels of uPA and IGF-1 mRNA were inversely related. No such correlation was found for uPA and IGF-2 mRNA. While exogen ously added IGF-I decreased the amount of uPA mRNA transcripts similarly in both normal and tumoral fibroblasts, exogenously added uPA decreased the a mount of IGF-1 mRNA transcripts only in tumor tissue-derived fibroblasts. T hese data suggest that in human breast fibroblasts IGF-1 controls the expre ssion of uPA and that, possibly due to an altered sensitivity to uPA, tumor -associated fibroblasts have escaped this local control mechanism. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.