SYNTHETIC ANTIESTROGENS MODULATE INDUCTION OF PS2 AND CATHEPSIN-D MESSENGER-RIBONUCLEIC-ACID BY GROWTH-FACTORS AND ADENOSINE-3',5'-MONOPHOSPHATE IN MCF7 CELLS

In MCF7 human breast cancer cells, the antiestrogens 4-hydroxytamoxife n and ICI 164,384 inhibit the mitogenic activity of epidermal growth f actor (EGF) and insulin-like growth factor-I (IGF-I). These growth fac tors also stimulate the expression of cathepsin-D and pS2 genes. There fore, we studied the effects of antiestrogens on growth factor inducti on of pS2 and cathepsin-D mRNA. The two antiestrogens strongly inhibit ed the transcriptional induction of pS2 by growth factors. On the cont rary, estradiol and IGF-I or EGF had an additive effect on pS2 mRNA ac cumulation. Growth factor induction of cathepsin-D was also inhibited by ICI 164,384. By contrast, 4-hydroxytamoxifen had an agonist effect on cathepsin-D and an additive effect on IGF-I-induced mRNA. When 12-0 -tetradecanoyphorbol-13-acetate or 8-bromo-cAMP (8-Br-cAMP) was used i nstead of growth factors, similar effects of 4-hydroxytamoxifen and IC I 164,384 were obtained on pS2 (12-0-tetradecanoyphorbol-13-acetate an d 8-Br-cAMP) and cathepsin-D (8-Br-cAMP) induction. A mechanism based on the classical competitive inhibition by antiestrogens of estrogen b inding and action on the estrogen receptor was very unlikely, as 1) no antigrowth factor activity was obtained with R5020, which was a poten t inhibitor of estrogen induction of pS2 and cathepsin-D mRNA; 2) in t he Ishikawa endometrial cancer cell line, the cathepsin-D gene is unre sponsive to estrogen, but was inhibited by antiestrogen after its indu ction by EGF or 8-Br-cAMP; and 3) the residual estrogen concentration in cells was too low to induce the expression of estrogen-specific gen es. However, antiestrogens did not inhibit the expression of all genes induced by growth factors, as they were without effect on IGF-I induc tion of glyceraldehyde-3-phosphate dehydrogenase mRNA. These results d emonstrate that antiestrogens can modulate the transcription of some g rowth factor-induced genes and strongly suggest that this effect is no t due to interference with residual estrogens.