Human breast fibroblasts have been shown to express urokinase-type plasminogen activator (uPA). This suggests that fibroblasts are actively involved in the process of uPA-directed breast tumor proteolysis. To investigate a possible role for the insulin-like growth factors (IGFs) in regulating uPA expression in human breast fibroblasts, we correlated the expression of uPA with 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 transcribed polymerase chain reaction (RT-PCR) amplified mRNA revealed that the tumor-derived fibroblast strain expressed significantly more basal uPA mRNA and significantly less IGF-1 mRNA when compared to their normal counterpart. The expression of basal IGF-2 mRNA did not differ between these cultures. For both normal and tumor tissue-derived fibroblasts, cytokine- and growth 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 exogenously added IGF-1 decreased the amount of uPA mRNA transcripts similarly in both normal and tumoral fibroblasts, exogenously added uPA decreased the amount of IGF-1 mRNA transcripts only in tumor tissue-derived fibroblasts. These data suggest that in human breast fibroblasts IGF-1 controls the expression of uPA and that, possibly due to an altered sensitivity to uPA, tumor-associated fibroblasts have escaped this local control mechanism.