Abstract
17β-Estradiol (E2), diethylstilbestrol (DES) and several synthetic (or xenoestrogenic) compounds induced transactivation in MCF-7 or MDA-MB-231 cells transfected with wild-type estrogen receptor α (ERα) and a construct (pERE3) containing three tandem estrogen responsive elements (EREs) linked to a luciferase gene. In contrast, the antiestrogens ICI 182,780 and 4-hydroxytamoxifen (4-OHT) were inactive in this assay. We have investigated the effects of these compounds and several structurally-diverse estrogenic compounds on transactivation in cells transfected with pERE3 and wild-type ERα, mutant ERα (1-553), and ERα (1-537) containing deletions of amino acids 595-554 and 595-538, respectively. These constructs were used to develop an in vitro assay to distinguish between different structural classes of estrogenic compounds. The results obtained using these constructs were highly cell context- and structure-dependent. Neither E2- nor diethylstilbestrol-induced transactivation in MCF-7 (or MDA-MB-231) cells transfected with pERE3/ERα (1-537) due to partial deletion of helix 12; however, octylphenol and nonlylphenol, resveratrol (a phytoestrogen), kepone and 2′,3′,4′,5′-tetrachloro-4-biphenylol were "estrogenic" in MCF-7 cells transfected with pERE3/ERα (1-537). Moreover, the structure-dependent estrogenic activities of several synthetic estrogens (xenoestrogens) in MDA-MB-231 cells were different than those observed in MCF-7 cells. These results demonstrate that the estrogenic activity of many synthetic compounds do not require activation function 2 (AF-2) of ERα and are mechanistically different from E2. These data suggest that xenoestrogens are selective ER modulators (SERMs).
Original language | English (US) |
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Pages (from-to) | 1-9 |
Number of pages | 9 |
Journal | Journal of Steroid Biochemistry and Molecular Biology |
Volume | 103 |
Issue number | 1 |
DOIs | |
State | Published - Jan 2007 |
Keywords
- ERα
- SERMs
- Transactivation
- Xenoestrogens
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism
- Biochemistry
- Molecular Medicine
- Molecular Biology
- Endocrinology
- Clinical Biochemistry
- Cell Biology