Schneider J, Huh M M, Bradlow H L, Fishman J
J Biol Chem. 1984 Apr 25;259(8):4840-5.
The estrogen responsive human breast cancer MCF-7 cell culture was examined for its response to 2-hydroxyestrone a principal metabolite of estradiol. Addition of 2-hydroxyestrone to the cell cultures in concentration of 10(-9) - 10(-6) M had no effect on cell growth and proliferation because of rapid O-methylation of the catechol estrogen by catechol O-methyltransferase which is highly active in these cells. In the presence of quinalizarin, a potent catechol O-methyltransferase inhibitor which reduces the O-methylation of the steroid, 10(-7) M and 10(-8) M 2-hydroxyestrone markedly suppresses the growth and proliferation of the cells. The tumor cell growth-inhibitory action of the catechol estrogen was neutralized by the presence of 10(-9) M estradiol. The catechol estrogen inhibition of cell growth is not observed in the estrogen receptor-negative human breast cancer cell lines MDA-MB-231 and MDA-MB-330 providing evidence that the inhibition is specific and is estrogen receptor-mediated. In contrast, the 16 alpha-hydroxylated metabolites of estradiol, estriol and 16 alpha-hydroxyestrone, are effective stimulators of MCF-7 cell proliferation with the latter exhibiting potency in excess of that expected from its estrogen receptor affinity. The present results represent the first observation of a specific receptor-mediated antiestrogenic action of 2-hydroxyestrone and suggest that the physiological regulation of the agonist activity of the primary estrogen may involve in situ generation of catechol estrogen.
对雌激素反应性人乳腺癌MCF - 7细胞培养物进行检测，以观察其对雌二醇的主要代谢产物2 - 羟基雌酮的反应。向细胞培养物中添加浓度为10(-9) - 10(-6) M的2 - 羟基雌酮对细胞生长和增殖没有影响，因为儿茶酚雌激素在这些细胞中高度活跃的儿茶酚O - 甲基转移酶作用下会迅速发生O - 甲基化。在存在茜素红（一种有效的儿茶酚O - 甲基转移酶抑制剂，可减少类固醇的O - 甲基化）的情况下，10(-7) M和10(-8) M的2 - 羟基雌酮能显著抑制细胞的生长和增殖。10(-9) M的雌二醇存在时，儿茶酚雌激素的肿瘤细胞生长抑制作用被中和。在雌激素受体阴性的人乳腺癌细胞系MDA - MB - 231和MDA - MB - 330中未观察到儿茶酚雌激素对细胞生长的抑制作用，这证明该抑制作用具有特异性且是由雌激素受体介导的。相比之下，雌二醇的16α - 羟基化代谢产物、雌三醇和16α - 羟基雌酮是MCF - 7细胞增殖的有效刺激剂，其中后者表现出的效力超过了根据其雌激素受体亲和力所预期的效力。目前的结果首次观察到2 - 羟基雌酮具有特异性受体介导的抗雌激素作用，并表明主要雌激素激动剂活性的生理调节可能涉及儿茶酚雌激素的原位生成。
