Simard J, Dauvois S, Haagensen D E, Lévesque C, Mérand Y, Labrie F
Medical Research Council Group in Molecular Endocrinology, CHUL Research Center, Quebec, Canada.
Endocrinology. 1990 Jun;126(6):3223-31. doi: 10.1210/endo-126-6-3223.
We have previously demonstrated that androgens are potent inhibitors of breast cancer cell proliferation under both basal and estrogen-induced incubation conditions, while they suppress expression of the estrogen and progesterone receptors. To better understand the mechanisms responsible for the antagonism between androgens and estrogens in breast cancer and to obtain a new tumor marker for the actions of these two steroids, we have investigated the effects of androgens and estrogens on expression of the major protein found in human breast gross cystic disease fluid, namely GCDFP-24. This study was performed in ZR-75-1 and MCF-7 human breast cancer cells. After a 9-day incubation period, physiological concentrations of 17 beta-estradiol stimulated proliferation of ZR-75-1 and MCF-7 cells by 2- to 3.5-fold while simultaneously exerting a marked 70-90% inhibition of GCDFP-24 secretion. The estrogenic effects on GCDFP-24 secretion and cell proliferation were both competitively blocked by simultaneous incubation with the new steroidal pure antiestrogen EM-139. On the other hand, a maximal concentration (10 nM) of the nonaromatizable androgen dihydrotestosterone decreased by 50% the proliferation of ZR-75-1 cells; the half-maximal inhibitory effect was exerted at 0.01 nM. The androgen exerted a 3- to 4-fold stimulatory effect on GCDFP-24 secretion at an EC50 value of 0.01 nM. The effect of dihydrotestosterone on these parameters was competitively blocked by simultaneous incubation with the pure antiandrogen OH-flutamide. The present data show that the effects of estrogens and androgens in ZR-75-1 cells on GCDFP-24 secretion and cell growth are opposite. Similarly, in MCF-7 cells, estrogens stimulate cell growth, while GCDFP-24 secretion is inhibited. The present data also suggest that GCDFP-24 could well be a good biochemical marker for monitoring the response to androgenic and antiestrogenic compounds in the therapy of advanced breast cancer.
我们先前已经证明，在基础培养条件以及雌激素诱导的培养条件下，雄激素都是乳腺癌细胞增殖的有效抑制剂，同时它们还能抑制雌激素和孕激素受体的表达。为了更好地理解雄激素与雌激素在乳腺癌中相互拮抗的机制，并获得这两种甾体激素作用的新肿瘤标志物，我们研究了雄激素和雌激素对人乳腺大囊性病液中主要蛋白质（即GCDFP - 24）表达的影响。本研究在ZR - 75 - 1和MCF - 7人乳腺癌细胞中进行。经过9天的培养期，生理浓度的17β - 雌二醇使ZR - 75 - 1和MCF - 7细胞的增殖增加了2至3.5倍，同时对GCDFP - 24的分泌产生了显著的70 - 90%的抑制作用。雌激素对GCDFP - 24分泌和细胞增殖的作用都被与新型甾体纯抗雌激素EM - 139同时孵育竞争性阻断。另一方面，不可芳香化的雄激素二氢睾酮的最大浓度（10 nM）使ZR - 75 - 1细胞的增殖减少了50%；半数最大抑制效应在0.01 nM时出现。雄激素在0.01 nM的EC50值下对GCDFP - 24的分泌产生了3至4倍的刺激作用。二氢睾酮对这些参数的作用被与纯抗雄激素OH - 氟他胺同时孵育竞争性阻断。目前的数据表明，雌激素和雄激素对ZR - 75 - 1细胞中GCDFP - 24分泌和细胞生长的作用是相反的。同样，在MCF - 7细胞中，雌激素刺激细胞生长，而GCDFP - 24的分泌受到抑制。目前的数据还表明，GCDFP - 24很可能是监测晚期乳腺癌治疗中对雄激素和抗雌激素化合物反应的良好生化标志物。
