Estrogenic and antiestrogenic activities of 16α- and 2-hydroxy metabolites of 17β-estradiol in MCF-7 and T47D human breast cancer cells

被引:79
作者
Gupta, M [1 ]
McDougal, A [1 ]
Safe, S [1 ]
机构
[1] Texas A&M Univ, Dept Vet Physiol & Pharmacol, College Stn, TX 77843 USA
关键词
D O I
10.1016/S0960-0760(98)00135-6
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The comparative mitogenic activities of 17 beta-estradiol (E2) and four metabolites, 2-hydroxyestradiol (2-OHE2), 2-hydroxyestrone (2-OHE1), 16 alpha-hydroxyestradiol (16 alpha-OHE2) and 16 alpha-hydroxyestrone (16 alpha-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 16 alpha-OHE1 or 16 alpha-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, 16 alpha-OHE2 and 16 alpha-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 clot 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 16 alpha-OHE1/16 alpha-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). (C) 1999 Elsevier Science Ltd. All rights reserved.
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收藏
页码:413 / 419
页数:7
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