IN-VITRO INVASIVENESS OF HUMAN BREAST-CANCER CELLS THROUGH PLASMINOGEN-ACTIVATOR ACTIVITY INDEPENDENTLY REGULATED BY HORMONES AND TRANSFORMING GROWTH-FACTOR-BETA-1

Background - Proteolytic events, especially plasminogen activator (PA) -mediated fibrinolytic activation, are known to participate in cancer invasion and metastasis, and the production and release of PA by cance r cells may be affected by various hormones and cytokines. Methods - W e investigated the relationship between the in-vitro invasiveness of h uman breast cancer cells (MCF-7 and MDA-MB-231) in a reconstituted mat rix containing plasminogen and their PA production with emphasis on th e influence of hormones and transforming growth factor (TGF)-beta 1. R esults - Not only the production of tissue-type (t-PA) and urokinase-t ype PA (u-PA), but also the invasiveness of MCF-7 cells was enhanced b y a factor of almost two by estrogen and this enhancement was blocked by simultaneous treatment with tamoxifen. Progesterone and prolactin s lightly stimulated t-PA production, but did not appear to affect invas iveness, The production of PA and the invasiveness of MDA-MB-231 cells , which produced more PA and were more invasive than the MCF-7 cells, were only affected by dexamethasone. t-PA and u-PA antibodies independ ently suppressed the invasiveness of both cell lines, Both PA producti on and invasiveness were enhanced by TGF-beta 1 in MCF-7 cells, but we re inhibited in MDA-MB-231 cells. Conclusion - Both t-PA u-PA play an important role in the in-vitro invasiveness of two different breast ca ncer cell lines through the PA-plasminogen-plasmin system; while estro gen enhances the invasiveness of MCF-7. cells by increasing the produc tion and release of both PA, probably via the estrogen receptor, In co ntrast, TGF-beta 1 appears to exert opposite effects on invasiveness t hrough PA production in the two cell types.