Estrogenic and antiestrogenic activities of 16alpha- and 2-hydroxy metabolites of 17beta-estradiol in MCF-7 and T47D human breast cancer cells.
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).
Gupta
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M
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station 77843-4466, USA.
McDougal
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Safe
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D001943:Breast Neoplasms; D002402:Cathepsin D / Q000096:biosynthesis / Q000235:genetics; D002455:Cell Division / Q000187:drug effects*; D003402:Creatine Kinase / Q000096:biosynthesis / Q000235:genetics; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004964:Estriol / Q000494:pharmacology; D005260:Female; D006801:Humans; D006894:Hydroxyestrones / Q000494:pharmacology; D007527:Isoenzymes; D011401:Promoter Regions, Genetic; D011960:Receptors, Estrogen / Q000502:physiology; D011994:Recombinant Proteins / Q000096:biosynthesis; D014162:Transfection; D014407:Tumor Cells, Cultured
D006894:Hydroxyestrones; D007527:Isoenzymes; D011960:Receptors, Estrogen; D011994:Recombinant Proteins; C026702:16-hydroxyestrone; D004958:Estradiol; C001390:2-hydroxyestradiol; D003402:Creatine Kinase; D002402:Cathepsin D; D004964:Estriol; C024980:2-hydroxyestrone