Differential activation of wild-type and variant forms of estrogen receptor alpha by synthetic and natural estrogenic compounds using a promoter containing three estrogen-responsive elements

Structure-dependent estrogen receptor alpha (ER alpha) agonist and antagoni st activities of synthetic and natural estrogenic compounds were investigat ed in human HepG2, MDA-MB-231 and U2 cancer cell lines. Compounds used in t his study include 4 ' -hydroxytamoxifen, ICI 182,780, bisphenol-A (BPA), 2 ' ,4 ' ,6 ' -trichloro-4-biphenylol (3Cl-PCB-OH), 2 ' ,3 ' ,4 ' ,5 ' -tetra chloro-4-biphenylol (4Cl-PCB-OH), p-t-octylphenol, p-nonylphenol, naringeni n, kepone, resveratrol, and 2,2-bis(p-hydroxyphehyl)-1,1,1-trichloroethane (HPTE). Cells were transfected with a construct (pERE(3)) containing three tandem estrogen responsive elements (EREs) and either wild-type estrogen re ceptor a (ER-wt) or variants expressing activation function-1 (ER-AF1) or A F-2 (ER-AF2). The ER agonist activities of the synthetic mono and dihydroxy aromatic compounds are comparable in all three-cell lines, whereas the act ivities of naringenin, kepone and resveratrol are dependent on cell context and expression of wild-type or variant forms of ER alpha. In contrast, the ER antagonist activities for these compounds were highly complex and, with the exception of 3Cl-PCB-OH, all compounds inhibited E2-induced wild-type or variant ER action. Results of this in vitro study suggest that the estro genic and antiestrogenic activity of structurally diverse synthetic and nat ural estrogenic compounds is complex, and this is consistent with published data that often give contradictory results for these compounds. (C) 2001 E lsevier Science Ltd. All rights reserved.