Insulin-like growth factor 1 (IGF-1) and urokinase-type plasminogen activator (uPA) are inversely related in human breast fibroblasts.
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.
Sieuwerts
A M
AM
Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek)/Academic Hospital Rotterdam, The Netherlands. sieuwerts@bidh.azr.nl
Klijn
J G
JG
Foekens
J A
JA
D001940:Breast / Q000737:chemistry* / Q000166:cytology; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000737:chemistry*; D015870:Gene Expression; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*
D016207:Cytokines; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D014568:Urokinase-Type Plasminogen Activator