title: Cell proliferation and modulation of interaction of estrogen receptors with coregulators induced by ERα and ERβ agonists.
abstract: The aim of the present study was to investigate modulation of the interaction of the ERα and ERβ with coregulators in the ligand responses induced by estrogenic compounds. To this end, selective ERα and ERβ agonists were characterized for intrinsic relative potency reflected by EC50 and maximal efficacy towards ERα and ERβ mediated response in ER selective reporter gene assays, and subsequently tested for induction of cell proliferation in T47D-ERβ cells with variable ERα/ERβ ratio, and finally for ligand dependent modulation of the interaction of ERα and ERβ with coregulators using the MARCoNI assay, with 154 unique nuclear receptor coregulator peptides derived from 66 different coregulators. Results obtained reveal an important influence of the ERα/ERβ ratio and receptor selectivity of the compounds tested on induction of cell proliferation. ERα agonists activate cell proliferation whereas ERβ suppresses ERα mediated cell proliferation. The responses in the MARCoNI assay reveal that upon ERα or ERβ activation by a specific agonist, the modulation of the interaction of the ERs with coregulators is very similar indicating only a limited number of differences upon ERα or ERβ activation by a specific ligand. Differences in the modulation of the interaction of the ERs with coregulators between the different agonists were more pronounced. Based on ligand dependent differences in the modulation of the interaction of the ERs with coregulators, the MARCoNI assay was shown to be able to classify the ER agonists discriminating between different agonists for the same receptor, a characteristic not defined by the ER selective reporter gene or proliferation assays. It is concluded that the ultimate effect of the model compounds on proliferation of estrogen responsive cells depends on the intrinsic relative potency of the agonist towards ERα and ERβ and the cellular ERα/ERβ ratio whereas differences in the modulation of the interaction of the ERα and ERβ with coregulators contribute to the ligand dependent responses induced by estrogenic compounds.
authors.affiliation: Division of Toxicology, Wageningen University, Tuinlaan 5, 6703 HE Wageningen, the Netherlands. Electronic address: nynke.m.evers@gmail.com.
authors.forename: Nynke M
authors.initials: NM
authors.lastname: Evers
authors.affiliation: Division of Toxicology, Wageningen University, Tuinlaan 5, 6703 HE Wageningen, the Netherlands.
authors.forename: Johannes H J
authors.initials: JH
authors.lastname: van den Berg
authors.affiliation: Division of Toxicology, Wageningen University, Tuinlaan 5, 6703 HE Wageningen, the Netherlands.
authors.forename: Si
authors.initials: S
authors.lastname: Wang
authors.affiliation: PamGene International B.V., Wolvenhoek 10, 5211 HH 's Hertogenbosch, the Netherlands.
authors.forename: Diana
authors.initials: D
authors.lastname: Melchers
authors.affiliation: PamGene International B.V., Wolvenhoek 10, 5211 HH 's Hertogenbosch, the Netherlands.
authors.forename: René
authors.initials: R
authors.lastname: Houtman
authors.affiliation: Division of Toxicology, Wageningen University, Tuinlaan 5, 6703 HE Wageningen, the Netherlands.
authors.forename: Laura H J
authors.initials: LH
authors.lastname: de Haan
authors.affiliation: Pharmacokinetics Pharmacodynamics & Drug Metabolism, MSD, P.O. Box 20, 5340 BH Oss, the Netherlands.
authors.forename: Antwan G H
authors.initials: AG
authors.lastname: Ederveen
authors.affiliation: Division of Toxicology, Wageningen University, Tuinlaan 5, 6703 HE Wageningen, the Netherlands; PamGene International B.V., Wolvenhoek 10, 5211 HH 's Hertogenbosch, the Netherlands.
authors.forename: John P
authors.initials: JP
authors.lastname: Groten
authors.affiliation: Division of Toxicology, Wageningen University, Tuinlaan 5, 6703 HE Wageningen, the Netherlands.
authors.forename: Ivonne M C M
authors.initials: IM
authors.lastname: Rietjens
mesh_terms: D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D047628:Estrogen Receptor alpha / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D006801:Humans; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D020845:Selective Estrogen Receptor Modulators
keywords: Cell proliferation; Coregulators; ERA-45; ERB-041; ERα; ERβ; Estradiol; Genistein