Over the past two decades, we have learned that estrogens play important physiological roles not only in women but also in men and that the biological effects of estrogen are mediated by not one but ...two distinct estrogen receptors (ERs), ERα and ERβ. Our appreciation of the physiological importance of estrogen and the mechanisms by which it acts has significantly increased over the years; however, we are only now beginning to decipher the roles of ERα and ERβ in different organs and to elucidate how selective ligands, acting through either of the two ERs, can prevent or treat various age‐ or sex‐specific diseases. The specific roles of ERα and ERβ and the therapeutic potential of ER subtype–selective agonists in bone and metabolic homeostasis, depression, vasomotor symptoms, neurodegenerative diseases, and cancer are reviewed herein. It must be stated, however, that appropriate clinical studies are necessary to validate these compounds as agents for the prevention and treatment of diseases.
Clinical Pharmacology & Therapeutics (2011) 89 1, 44–55. doi: 10.1038/clpt.2010.226
We demonstrate a computational network model that integrates 18 in vitro, high-throughput screening assays measuring estrogen receptor (ER) binding, dimerization, chromatin binding, transcriptional ...activation, and ER-dependent cell proliferation. The network model uses activity patterns across the in vitro assays to predict whether a chemical is an ER agonist or antagonist, or is otherwise influencing the assays through a manner dependent on the physics and chemistry of the technology platform ("assay interference"). The method is applied to a library of 1812 commercial and environmental chemicals, including 45 ER positive and negative reference chemicals. Among the reference chemicals, the network model correctly identified the agonists and antagonists with the exception of very weak compounds whose activity was outside the concentration range tested. The model agonist score also correlated with the expected potency class of the active reference chemicals. Of the 1812 chemicals evaluated, 111 (6.1%) were predicted to be strongly ER active in agonist or antagonist mode. This dataset and model were also used to begin a systematic investigation of assay interference. The most prominent cause of false-positive activity (activity in an assay that is likely not due to interaction of the chemical with ER) is cytotoxicity. The model provides the ability to prioritize a large set of important environmental chemicals with human exposure potential for additional in vivo endocrine testing. Finally, this model is generalizable to any molecular pathway for which there are multiple upstream and downstream assays available.
Breast cancer (BC) is the most common cancer among women worldwide. More than 70% of BC cases express estrogen receptor alpha (ERα), a central transcription factor that stimulates the proliferation ...of breast cancer cells, usually in the presence of estrogen. While most cases of ER-positive BC initially respond to antiestrogen therapies, a high percentage of cases develop resistance to treatment over time. The recent discovery of mutated forms of ERα that result in constitutively active forms of the receptor in the metastatic-resistance stage of BC has provided a strong rationale for the development of new antiestrogens. These molecules targeting clinically relevant ERα mutants and a combination with other pharmacological inhibitors of specific pathways may constitute alternative treatments to improve clinical practice in the fight against metastatic-resistant ER-positive BC. In this review, we summarize the latest advances regarding the particular involvement of point mutations of ERα in endocrine resistance. We also discuss the involvement of synonymous ERα mutations with respect to co-translational folding of the receptor and ribosome biogenesis in breast carcinogenesis.
•Estrogens exert both beneficial and negative actions in humans.•The actions of estrogens are mediated by two receptor subtypes (ERα and ERβ).•The ligand binding pockets of ERα and ERβ are highly ...similar.•The most promising ER-ligands for new clinical uses are ERβ-selective agonists.•So far, no ERβ-selective agonists have been successfully introduced into the clinic.
Estrogen receptors alpha (ERα) and beta (ERβ) are nuclear transcription factors that are involved in the regulation of many complex physiological processes in humans. Modulation of these receptors by prospective therapeutic agents is currently being considered for prevention and treatment of a wide variety of pathological conditions, such as, cancer, metabolic and cardiovascular diseases, neurodegeneration, inflammation, and osteoporosis. This review provides an overview and update of compounds that have been recently reported as modulators of ERs, with a particular focus on their potential clinical applications.
Estrogen receptors (ERs) are typical members of the superfamily of nuclear receptors that mainly function as ligand-inducible transcription factors that bind chromatin, as homodimers, at specific ...response elements. A tight reciprocal coupling between rapid ‘non-genomic’ and ‘genomic’ ER actions may also occur in many physiological processes. ERs have long been evaluated for their roles in controlling the expression of genes involved in vital cellular processes such as proliferation, apoptosis, and differentiation. Therefore, given the various and pleiotropic functions of ERs, the dysregulation of their pathways contributes to several diseases such as the hormone-dependent breast; endometrial and ovarian cancers; and neurodegenerative diseases, cardiovascular diseases, and osteoporosis. In this printed edition of the Special Issue, “Molecular Pathways of Estrogen Receptor Action”, promising results on understanding the mechanisms underlying ER-mediated effects in various pathophysiological processes are represented, covering different roles of ER pathways in the tumorigenesis, the resistance to endocrine therapy, the dynamics of 3D genome organization, and cross-talk with other signaling pathways. This Special Issue also provides insight into the emerging roles of estrogen-signaling pathways in lung cancer, the tumor microenvironment, and the immune system.
The estrogen receptors, ERα, ERβ, and GPER, mediate the effects of estrogenic compounds on their target tissues. Estrogen receptors are located in the tissues of the female reproductive tract and ...breast as one would expect, but also in tissues as diverse as bone, brain, liver, colon, skin, and salivary gland. The purpose of this discussion of the estrogen receptors is to provide a brief overview of the estrogen receptors and estrogen action from perspectives such as the historical, physiological, pharmacological, pathological, structural, and ligand perspectives.
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•Glyphosate at 10−12 to 10−6M promoted growth of T47D cells via estrogen receptors.•Glyphosate produced the activation of ERE which can be blocked by ICI 182780.•Glyphosate altered ...estrogen receptors by increasing expression ratio of ERα and ERβ.•Glyphosate had an additive effect with genistein on ERE activation and cell growth.
Glyphosate is an active ingredient of the most widely used herbicide and it is believed to be less toxic than other pesticides. However, several recent studies showed its potential adverse health effects to humans as it may be an endocrine disruptor. This study focuses on the effects of pure glyphosate on estrogen receptors (ERs) mediated transcriptional activity and their expressions. Glyphosate exerted proliferative effects only in human hormone-dependent breast cancer, T47D cells, but not in hormone-independent breast cancer, MDA-MB231 cells, at 10−12 to 10−6M in estrogen withdrawal condition. The proliferative concentrations of glyphosate that induced the activation of estrogen response element (ERE) transcription activity were 5-13 fold of control in T47D-KBluc cells and this activation was inhibited by an estrogen antagonist, ICI 182780, indicating that the estrogenic activity of glyphosate was mediated via ERs. Furthermore, glyphosate also altered both ERα and β expression. These results indicated that low and environmentally relevant concentrations of glyphosate possessed estrogenic activity. Glyphosate-based herbicides are widely used for soybean cultivation, and our results also found that there was an additive estrogenic effect between glyphosate and genistein, a phytoestrogen in soybeans. However, these additive effects of glyphosate contamination in soybeans need further animal study.
Breast cancer, a most common malignancy in women, was known to be associated with steroid hormone estrogen. The discovery of estrogen receptor (ER) gave us not only a powerful predictive and ...prognostic marker, but also an efficient target for the treatment of hormone-dependent breast cancer with various estrogen ligands. ER consists of two subtypes i.e. ERα and ERβ, that are mostly G-protein-coupled receptors and activated by estrogen, specially 17β-estradiol. The activation is followed by translocation into the nucleus and binding with DNA to modulate activities of different genes. ERs can manage synthesis of RNA through genomic actions without directly binding to DNA. Receptors are tethered by protein-protein interactions to a transcription factor complex to communicate with DNA. Estrogens also exhibit nongenomic actions, a characteristic feature of steroid hormones, which are so rapid to be considered by the activation of RNA and translation. These are habitually related to stimulation of different protein kinase cascades. Majority of post-menopausal breast cancer is estrogen dependent, mostly potent biological estrogen (E2) for continuous growth and proliferation. Estrogen helps in regulating the differentiation and proliferation of normal breast epithelial cells. In this review we have investigated the important role of ER in development and progression of breast cancer, which is complicated by receptor's interaction with co-regulatory proteins, cross-talk with other signal transduction pathways and development of treatment strategies viz. selective estrogen receptor modulators (SERMs), selective estrogen receptor down regulators (SERDs), aromatase and sulphatase inhibitors.
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•ERs, a type of GPCR, which are activated by estrogen hormone, specially 17β-estradiol (E2).•Zinc finger sub domains comprised of 8 cysteine residues, having coordination with two Zn+2 ions.•DNA binding domain, often referred as hinge region, contains receptor dimerisation sequences.•Crosstalk between ERs and EGF, HER-2, IGF-1and PI3K is critical for developing resistance of antiestrogens.
About 70% of breast tumors express estrogen receptor alpha (ERα), which mediates the proliferative effects of estrogens on breast epithelial cells, and are candidates for treatment with ...antiestrogens, steroidal or non-steroidal molecules designed to compete with estrogens and antagonize ERs. The variable patterns of activity of antiestrogens (AEs) in estrogen target tissues and the lack of systematic cross-resistance between different types of molecules have provided evidence for different mechanisms of action. AEs are typically classified as selective estrogen receptor modulators (SERMs), which display tissue-specific partial agonist activity (e.g. tamoxifen and raloxifene), or as pure AEs (e.g. fulvestrant), which enhance ERα post-translational modification by ubiquitin-like molecules and accelerate its proteasomal degradation. Characterization of second- and third-generation AEs, however, suggests the induction of diverse ERα structural conformations, resulting in variable degrees of receptor downregulation and different patterns of systemic properties in animal models and in the clinic.
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