Chemico-Biological Interactions 2014-09-05

Identification of coregulators influenced by estrogen receptor subtype specific binding of the ER antagonists 4-hydroxytamoxifen and fulvestrant.

Nynke M Evers, Si Wang, Johannes H J van den Berg, René Houtman, Diana Melchers, Laura H J de Haan, Antwan G H Ederveen, John P Groten, Ivonne M C M Rietjens

Index: Chem. Biol. Interact. 220 , 222-30, (2014)

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Abstract

The aim of the present study was to investigate modulation of the interaction of ERα and ERβ with coregulators in the ligand dependent responses induced by the ER antagonistic compounds 4OHT and fulvestrant. Comparison with the modulation index (MI) profiles for the ER agonist estradiol (E2) will elucidate whether differences in the (ant)agonist dependent interaction of ERα and ERβ with coregulators expressed in MI profiles contribute to the differences in (ant)agonist responses. To this end, the selected ER antagonistic compounds were first characterized for intrinsic relative potency and efficacy towards ERα and ERβ using ER selective U2OS reporter gene assays, and subsequently tested for ligand dependent modulation of the interaction of ERα and ERβ with coregulators using the MARCoNI assay. Results obtained indicate a preference of 4OHT to antagonize ERβ and find fulvestrant to be less ER specific. MARCoNI assay responses reveal that ERα and ERβ mediated interaction with coregulators expressed in MI profiles are similar for 4OHT and fulvestrant and generally opposite to the MI profile of the ER agonist E2. Hierarchical clustering based on the MI profiles appeared able to clearly discriminate the two compounds with ER antagonistic properties from the ER agonist E2. Taken together the data reveal that modulation of the interaction of ERs with coregulators discriminates ER agonists from antagonists but does not discriminate between the less specific ER antagonist fulvestrant and the preferential ERβ antagonistic compound 4OHT. It is concluded that differences in modulation of the interaction of ERα and ERβ with coregulators contribute to the differences in ligand dependent responses induced by ER agonists and ER antagonists but the importance of the subtle differences in modulation of the interaction of ERs with coregulators between the ER antagonistic compounds 4OHT and fulvestrant for the ultimate biological effect remains to be established. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.