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

Abstract

Estrogens produce biological effects by interacting with two estrogen receptors, ERα and ERβ. Drugs that selectively target ERα or ERβ might be safer for conditions that have been traditionally treated with non-selective estrogens. Several synthetic and natural ERβ-selective compounds have been identified. One class of ERβ-selective agonists is represented by ERB-041 (WAY-202041) which binds to ERβ much greater than ERα. A second class of ERβ-selective agonists derived from plants include MF101, nyasol and liquiritigenin that bind similarly to both ERs, but only activate transcription with ERβ. Diarylpropionitrile represents a third class of ERβ-selective compounds because its selectivity is due to a combination of greater binding to ERβ and transcriptional activity. However, it is unclear if these three classes of ERβ-selective compounds produce similar biological activities. The goals of these studies were to determine the relative ERβ selectivity and pattern of gene expression of these three classes of ERβ-selective compounds compared to estradiol (E2), which is a non-selective ER agonist. U2OS cells stably transfected with ERα or ERβ were treated with E2 or the ERβ-selective compounds for 6 h. Microarray data demonstrated that ERB-041, MF101 and liquiritigenin were the most ERβ-selective agonists compared to estradiol, followed by nyasol and then diarylpropionitrile. FRET analysis showed that all compounds induced a similar conformation of ERβ, which is consistent with the finding that most genes regulated by the ERβ-selective compounds were similar to each other and E2. However, there were some classes of genes differentially regulated by the ERβ agonists and E2. Two ERβ-selective compounds, MF101 and liquiritigenin had cell type-specific effects as they regulated different genes in HeLa, Caco-2 and Ishikawa cell lines expressing ERβ. Our gene profiling studies demonstrate that while most of the genes were commonly regulated by ERβ-selective agonists and E2, there were some genes regulated that were distinct from each other and E2, suggesting that different ERβ-selective agonists might produce distinct biological and clinical effects.

Estrogen receptor-beta agonist diarylpropionitrile counteracts the estrogenic activity of estrogen receptor-alpha agonist propylpyrazole-triol in the mammary gland of ovariectomized Sprague Dawley rats

“…In addition, the effect of ER␤ on cellular activities of target cells is ligand type dependent and the results from ER␤-selective agonists including DPN may not represent the physiological role of ER␤ bound to estrogen [9,47,53,54]. The effect of DPN on mammary cell proliferation in this study is quite different from that of the ER␤-selective agonist BAG in the study by Cheng et al using an OVX mouse model [30].…”

“…In addition to genetic modification of estrogen receptor expression, ER-selective agonists have been developed to determine the biological functions of ER␣ and ER␤ [9,47,[53][54][55]. These ER-selective agonists may also be used for pharmacological interventions of estrogenic activity [9,53,55].…”

Estrogen receptor β agonist enhances temozolomide sensitivity of glioma cells by inhibiting PI3K/AKT/mTOR pathway

“…ERα has been shown to enhance the proliferation of cancer cells (10)(11)(12), while previous studies support the role of ERβ as a potential tumor suppressor (7,10,13,14). Loss of ERβ expression has been repeatedly observed in high-grade glioma tumors and is associated with poor clinical outcome (10,14,15). A previous study also revealed that overexpression of ERβ reduced cell proliferation in colon and breast cancer cells while knockdown of ERβ exhibited the opposite effect (13).…”

“…There are two main types of cognate receptors of estrogens, ERα and ERβ, which selectively bind to different ligands and mediate the expression of different downstream genes and signaling cascades (7,9,10). ERα has been shown to enhance the proliferation of cancer cells (10)(11)(12), while previous studies support the role of ERβ as a potential tumor suppressor (7,10,13,14). Loss of ERβ expression has been repeatedly observed in high-grade glioma tumors and is associated with poor clinical outcome (10,14,15).…”

Endocrine disruption of oestrogen action and female reproductive tract cancers

“…Briefly, ligand binding to ERa and ERb causes a conformational change in the shape of the protein that is different for agonists and antagonists (Paige et al 1999). An understanding of the 3D structure of both ERa and ERb has allowed chemists to develop receptor-selective agonists and antagonists (Sun et al 1999, Paruthiyil et al 2009). Furthermore, modelling of putative ligandreceptor interactions is now used for in silico screening allowing investigators to predict whether compounds are likely to interact with ERs (Biesiada et al 2011) and has been applied to environmental pollutants (Li et al 2012a).…”