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Cell proliferation and modulation of interaction of estrogen receptors with coregulators induced by ERα and ERβ

Nynke M Evers¹, Johannes H J van den Berg¹, Si Wang¹

¹Division of Toxicology, Wageningen University, Tuinlaan 5, 6703 HE Wageningen, the Netherlands.

The Journal of Steroid Biochemistry and Molecular Biology

|June 14, 2014

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.

Insights

Estrogenic compounds

Area of Science:

Endocrinology and molecular biology
Estrogen receptor signaling pathways

Background:

Estrogen receptors alpha (ERα) and beta (ERβ) are key regulators of gene expression.
Ligand-dependent interactions with coregulators modulate ERα and ERβ activity.
Understanding these interactions is crucial for developing targeted therapies.

Purpose of the Study:

To investigate how estrogenic compounds modulate ERα and ERβ interactions with coregulators.
To determine the influence of ERα/ERβ ratio and compound selectivity on cell proliferation.
To assess the utility of the MARCoNI assay in classifying ER agonists.

Main Methods:

Selective ERα and ERβ agonists were characterized for potency and efficacy.
Cell proliferation assays were performed in T47D-ERβ cells with varying ERα/ERβ ratios.
Ligand-dependent ERα/ERβ-coregulator interactions were analyzed using the MARCoNI assay.

Main Results:

ERα agonists promoted cell proliferation, while ERβ agonists suppressed it.
ERα/ERβ ratio significantly influenced cell proliferation responses.
The MARCoNI assay effectively classified ER agonists based on coregulator interaction modulation.
ERα and ERβ activation by specific agonists showed similar coregulator interaction patterns.

Conclusions:

Cellular ERα/ERβ ratio and agonist potency dictate estrogen-responsive cell proliferation.
Modulation of ERα/ERβ-coregulator interactions contributes to ligand-dependent responses.
The MARCoNI assay provides a valuable method for characterizing ER agonists.

Read full analysis

Keywords:

Cell proliferation Coregulators ERA-45 ERB-041 ERα ERβ Estradiol Genistein

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