Gupta M, McDougal A, Safe S
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station 77843-4466, USA.
J Steroid Biochem Mol Biol. 1998 Dec;67(5-6):413-9. doi: 10.1016/s0960-0760(98)00135-6.
The comparative mitogenic activities of 17beta-estradiol (E2) and four metabolites, 2-hydroxyestradiol (2-OHE2), 2-hydroxyestrone (2-OHE1), 16alpha-hydroxyestradiol (16alpha-OHE2) and 16alpha-hydroxyestrone (16alpha-OHE1) were determined in estrogen receptor (ER)-positive MCF-7 and T47D human breast cancer cells. E2 (1 nM) induced a 7- to 13-fold increase in cell number in both cell lines compared to untreated cells and the mitogenic potencies of 16alpha-OHE1 or 16alpha-OHE2 were comparable to or greater than E2. In contrast, 2-OHE1 and 2-OHE2 were weak mitogens in both cell lines and in cells cotreated with 1 nM E2 and 100 or 1000 nM 2-OHE1 or 2-OHE2, there was a significant inhibition of hormone-induced cell proliferation. The comparative ER agonist/antagonist activities of E2 and the metabolites on transactivation were determined in T47D cells transiently transfected with constructs containing promoter inserts from the cathepsin D (pCD) and creatine kinase B (pCKB) genes. E2, 16alpha-OHE2 and 16alpha-OHE1 induced reporter gene activity in both MCF-7 or T47D cells transfected with pCKB or pCD. In contrast, 2-OHE1 and 2-OHE2 did not exhibit ER agonist activity for these transactivation assays, but in cells cotreated with E2 plus 2-OHE1 or 2-OHE2, there was a significant decrease in the hormone-induced response. These results demonstrate that 16alpha-OHE1/16alpha-OHE2 exhibit estrogenic activities similar to that observed for E2, whereas the 2-catecholestrogens are weak ER agonists (cell proliferation) or antagonists (cell proliferation and transactivation).
在雌激素受体（ER）阳性的MCF-7和T47D人乳腺癌细胞中，测定了17β-雌二醇（E2）和四种代谢物2-羟基雌二醇（2-OHE2）、2-羟基雌酮（2-OHE1）、16α-羟基雌二醇（16α-OHE2）和16α-羟基雌酮（16α-OHE1）的相对促有丝分裂活性。与未处理的细胞相比，E2（1 nM）使两种细胞系中的细胞数量增加了7至13倍，且16α-OHE1或16α-OHE2的促有丝分裂能力与E2相当或更强。相比之下，2-OHE1和2-OHE2在两种细胞系中都是弱促有丝分裂剂，在与1 nM E2和100或1000 nM 2-OHE1或2-OHE2共同处理的细胞中，激素诱导的细胞增殖受到显著抑制。在瞬时转染了含有组织蛋白酶D（pCD）和肌酸激酶B（pCKB）基因启动子插入片段的构建体的T47D细胞中，测定了E2和这些代谢物对反式激活的相对ER激动剂/拮抗剂活性。E2、16α-OHE2和16α-OHE1在转染了pCKB或pCD的MCF-7或T47D细胞中均诱导了报告基因活性。相比之下，在这些反式激活试验中，2-OHE1和2-OHE2未表现出ER激动剂活性，但在与E2加2-OHE1或2-OHE2共同处理的细胞中，激素诱导的反应显著降低。这些结果表明，16α-OHE1/16α-OHE2表现出与E2类似的雌激素活性，而2-儿茶酚雌激素是弱ER激动剂（细胞增殖）或拮抗剂（细胞增殖和反式激活）。
