INDUCTION OF TISSUE-PLASMINOGEN ACTIVATOR MESSENGER-RNA AND ACTIVITY BY STRUCTURALLY ALTERED ESTROGENS

The effect of structure of the estrogen ligand on the accumulation of tPA mRNA and the activity of extracellular fibrinolytic enzyme has bee n examined in cultures of MCF-7 cells. Estradiol(E(2))-stimulated fibr inolytic activity was preceded by an increase in actinomycin D sensiti ve tPA mRNA synthesis which peaked at 18 h. Ten A- and D-ring structur al analogs of E(2) affected tPA mRNA accumulation and extracellular fi brinolytic activity. Only in the case of two A-ring isomers (2- and 4- hydroxyestratrien-17 beta-ol) was the decreased effect of the ligand's structural change on tPA mRNA accumulation and fibrinolysis not expla ined by a comparable decline in affinity of the ligand for estrogen re ceptor. Both of these analogs functioned as antiestrogens. The stimula tory capacity of androstanediols on the tPA gene required that the 3-h ydroxyl group be positioned in the beta-configuration. Absence of the 17 beta-hydroxy group was beneficial to the maximum accumulation of tP A mRNA. As has been reported for other estrogen responsive genes (prog esterone receptor, cathepsin D and pS2), regulation by estrogens is no t related directly to the affinity of the ligand for ER, but this acti vity may be determined by the location of the electronegative isopoten tial above the A-ring of estrogenic ligands.