Induction of tissue plasminogen activator mRNA 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 been examined in cultures of MCF-7 cells. Estradiol(E2)-stimulated fibrinolytic activity was preceded by an increase in actinomycin D sensitive tPA mRNA synthesis which peaked at 18 h. Ten A- and D-ring structural analogs of E2 affected tPA mRNA accumulation and extracellular fibrinolytic 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 explained by a comparable decline in affinity of the ligand for estrogen receptor. Both of these analogs functioned as antiestrogens. The stimulatory capacity of androstanediols on the tPA gene required that the 3-hydroxyl group be positioned in the beta-configuration. Absence of the 17 beta-hydroxy group was beneficial to the maximum accumulation of tPA mRNA. As has been reported for other estrogen responsive genes (progesterone receptor, cathepsin D and pS2), regulation by estrogens is not related directly to the affinity of the ligand for ER, but this activity may be determined by the location of the electronegative isopotential above the A-ring of estrogenic ligands.