Chalbos D, Philips A, Galtier F, Rochefort H
Unité Hormones et Cancer (U-148), INSERM, Montpellier, France.
Endocrinology. 1993 Aug;133(2):571-6. doi: 10.1210/endo.133.2.8344199.
In MCF7 human breast cancer cells, the antiestrogens 4-hydroxy-tamoxifen and ICI 164,384 inhibit the mitogenic activity of epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I). These growth factors also stimulate the expression of cathepsin-D and pS2 genes. Therefore, we studied the effects of antiestrogens on growth factor induction of pS2 and cathepsin-D mRNA. The two antiestrogens strongly inhibited the transcriptional induction of pS2 by growth factors. On the contrary, estradiol and IGF-I or EGF had an additive effect on pS2 mRNA accumulation. 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-O-tetradecanoylphorbol-13-acetate or 8-bromo-cAMP (8-Br-cAMP) was used instead of growth factors, similar effects of 4-hydroxytamoxifen and ICI 164,384 were obtained on pS2 (12-O-tetradecanoylphorbol-13-acetate and 8-Br-cAMP) and cathepsin-D (8-Br-cAMP) induction. A mechanism based on the classical competitive inhibition by antiestrogens of estrogen binding and action on the estrogen receptor was very unlikely, as 1) no antigrowth factor activity was obtained with R5020, which was a potent inhibitor of estrogen induction of pS2 and cathepsin-D mRNA; 2) in the Ishikawa endometrial cancer cell line, the cathepsin-D gene is unresponsive to estrogen, but was inhibited by antiestrogen after its induction by EGF or 8-Br-cAMP; and 3) the residual estrogen concentration in cells was too low to induce the expression of estrogen-specific genes. However, antiestrogens did not inhibit the expression of all genes induced by growth factors, as they were without effect on IGF-I induction of glyceraldehyde-3-phosphate dehydrogenase mRNA. These results demonstrate that antiestrogens can modulate the transcription of some growth factor-induced genes and strongly suggest that this effect is not due to interference with residual estrogens.
在MCF7人乳腺癌细胞中，抗雌激素药物4-羟基他莫昔芬和ICI 164,384可抑制表皮生长因子（EGF）和胰岛素样生长因子-I（IGF-I）的促有丝分裂活性。这些生长因子还可刺激组织蛋白酶-D和pS2基因的表达。因此，我们研究了抗雌激素药物对生长因子诱导pS2和组织蛋白酶-D mRNA的影响。这两种抗雌激素药物强烈抑制生长因子对pS2的转录诱导。相反，雌二醇与IGF-I或EGF对pS2 mRNA的积累具有相加作用。ICI 164,384也可抑制生长因子对组织蛋白酶-D的诱导。相比之下，4-羟基他莫昔芬对组织蛋白酶-D具有激动作用，对IGF-I诱导的mRNA具有相加作用。当使用12-氧十四烷酰佛波醇-13-乙酸酯或8-溴环磷酸腺苷（8-Br-cAMP）替代生长因子时，4-羟基他莫昔芬和ICI 164,384对pS2（12-氧十四烷酰佛波醇-13-乙酸酯和8-Br-cAMP）和组织蛋白酶-D（8-Br-cAMP）诱导产生类似的作用。基于抗雌激素药物对雌激素与雌激素受体结合及作用的经典竞争性抑制的机制极不可能，原因如下：1）强效抑制雌激素诱导pS2和组织蛋白酶-D mRNA的R5020未表现出抗生长因子活性；2）在石川子宫内膜癌细胞系中，组织蛋白酶-D基因对雌激素无反应，但在经EGF或8-Br-cAMP诱导后可被抗雌激素药物抑制；3）细胞内残留的雌激素浓度过低，无法诱导雌激素特异性基因的表达。然而，抗雌激素药物并未抑制所有生长因子诱导的基因表达，因为它们对IGF-I诱导甘油醛-3-磷酸脱氢酶mRNA无作用。这些结果表明，抗雌激素药物可调节某些生长因子诱导基因的转录，并强烈提示这种作用并非由于干扰残留雌激素所致。
