Drug and Cell Type-Specific Regulation of Genes with Different Classes of Estrogen Receptor β-Selective Agonists

Estrogens produce biological effects by interacting with two estrogen receptors, ER alpha and ER beta. Drugs that selectively target ERa or ERb might be safer for conditions that have been traditionally treated with non-selective estrogens. Several synthetic and natural ER beta-selective compounds have been identified. One class of ER beta-selective agonists is represented by ERB-041 (WAY-202041) which binds to ER beta much greater than ER alpha. A second class of ER beta-selective agonists derived from plants include MF101, nyasol and liquiritigenin that bind similarly to both ERs, but only activate transcription with ER beta. Diarylpropionitrile represents a third class of ER beta-selective compounds because its selectivity is due to a combination of greater binding to ER beta and transcriptional activity. However, it is unclear if these three classes of ER beta-selective compounds produce similar biological activities. The goals of these studies were to determine the relative ER beta selectivity and pattern of gene expression of these three classes of ER beta-selective compounds compared to estradiol (E(2)), which is a non-selective ER agonist. U2OS cells stably transfected with ER alpha or ER beta were treated with E(2) or the ER beta-selective compounds for 6 h. Microarray data demonstrated that ERB-041, MF101 and liquiritigenin were the most ER beta-selective agonists compared to estradiol, followed by nyasol and then diarylpropionitrile. FRET analysis showed that all compounds induced a similar conformation of ER beta, which is consistent with the finding that most genes regulated by the ER beta-selective compounds were similar to each other and E(2). However, there were some classes of genes differentially regulated by the ER beta agonists and E(2). Two ER beta-selective compounds, MF101 and liquiritigenin had cell type-specific effects as they regulated different genes in HeLa, Caco-2 and Ishikawa cell lines expressing ER beta. Our gene profiling studies demonstrate that while most of the genes were commonly regulated by ER beta-selective agonists and E(2), there were some genes regulated that were distinct from each other and E(2), suggesting that different ER beta-selective agonists might produce distinct biological and clinical effects.