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Glucocorticoid Modulation of Plasminogen Activators and of One of Their Inhibitors in the Human Mammary Carcinoma Cell Line MDA-MB-231¹

Institut d'Histologie et d'Embryologie [N. B., D. B., J-D. V.] and Département de Pathologie, [D. B.], Centre Médical Universitaire, Geneva, Switzerland, and the Institut de Recherches Scientifiques sur le Cancer [N. B., C. F-C.], Villejuif, France

In cultures of the human mammary carcinoma-derived cell line MDA-MB-231, plasminogen activator (PA) activity was reduced substantially following treatment with the glucocorticoid dexamethasone. These cells produced urokinase-type PA (u-PA) and tissue-type PA (t-PA), and both enzymes were decreased in dexamethasone-treated cultures. The drop in u-PA activity was associated with a decrease in the synthesis of singlechain pro-u-PA and in the concentration of u-PA messenger RNA; however, the decrease in u-PA activity was more extensive than could be accounted for by inhibition of enzyme synthesis only, suggesting that postsynthetic events were also involved. The comparatively small dexamethasone-induced decrease in t-PA activity was not associated with a change in the concentration of t-PA messenger RNA. Hence, the two PA genes are differentially regulated by the same hormone. MDA-MB-231 cells also produced a PA-specific inhibitor related to that produced by bovine aortic endothelial cells (PAI-1). This inhibitor was present in two forms: one functionally active, and the other which required activation by sodium dodecyl sulfate; both forms were increased in cultures exposed to dexamethasone: Thus, glucocorticoid-induced inhibition of PA activity in these cells results from a decrease in u-PA synthesis and a concomitant increase in the production of a PA inhibitor.

¹ This work was supported in part by grant 3.075-0.84 from the Swiss National Science Foundation and by a grant from the Sir Jules Thorn Charitable Trust.

² Recipient of a fellowship from Roussel-Uclaf laboratories. To whom requests for reprints should be addressed, at Institut d'Histologie et d'Embryologie, Centre Médical Universitaire, 1, rue Michel Servet, 1211 Geneva 4, Switzerland.

Received 7/ 7/86. Revised 9/12/86. Accepted 10/ 2/86.

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