title: Both N- and C-terminal transactivation functions of DNA-bound ERalpha are blocked by a novel synthetic estrogen ligand.
abstract: Estrogen receptors (ERs) play a central role in the diverse actions of estrogen. A number of synthetic ER ligands have been generated that can modulate various ER functions. Here we show that TAS-108, representing a novel class of synthetic ER ligands, blocked both ER transactivation functions without inhibiting DNA-binding activity. A transient expression assay showed that similar to ICI182,780, TAS-108 exhibited pure antagonistic activity as it blocked both the N-terminal AF-1 and C-terminal AF-2 transactivation functions. However, unlike ICI182,780, TAS-108 promoted the recruitment of the SMRT co-repressor that abolished ER transactivation function without inhibition of the ability of ERalpha to bind to its target DNA. Both TAS-108 and ICI182,780 acted as antagonists for the transactivation functions of the D351Y mutant, derived from tamoxifen-resistant breast cancer cells, while estrogen and known selective estrogen receptor modulators (SERMs), 4-OH tamoxifen and raloxifene, stimulated D351Y-mediated transcription. Thus, our findings indicated that TAS-108 acts as a novel estrogen antagonist that recruits co-repressors to ERs without AF-1 activation or prevention of DNA binding. Therefore, TAS-108 may be effective against tamoxifen-resistant breast cancer via a different mechanism than that for ICI182,780.
authors.affiliation: Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0032, Japan.
authors.forename: Yasuji
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Osamu
authors.initials: O
authors.lastname: Wada
authors.forename: Ichiro
authors.initials: I
authors.lastname: Takada
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Yogiashi
authors.forename: Jiro
authors.initials: J
authors.lastname: Shibata
authors.forename: Junn
authors.initials: J
authors.lastname: Yanagisawa
authors.forename: Kenji
authors.initials: K
authors.lastname: Kitazato
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Kato
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism*; D008024:Ligands; D009687:Nuclear Proteins / Q000378:metabolism; D011485:Protein Binding; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D017471:Receptors, Interferon / Q000378:metabolism; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects* / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; C086185:IFNGR2 protein, human; D008024:Ligands; D009687:Nuclear Proteins; D011960:Receptors, Estrogen; D017471:Receptors, Interferon; C482068:TS 108; D015534:Trans-Activators; D004958:Estradiol