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Annual Review of Pathology Jan 2022Triple-negative breast cancer (TNBC) encompasses a heterogeneous group of fundamentally different diseases with different histologic, genomic, and immunologic profiles,... (Review)
Review
Triple-negative breast cancer (TNBC) encompasses a heterogeneous group of fundamentally different diseases with different histologic, genomic, and immunologic profiles, which are aggregated under this term because of their lack of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression. Massively parallel sequencing and other omics technologies have demonstrated the level of heterogeneity in TNBCs and shed light into the pathogenesis of this therapeutically challenging entity in breast cancer. In this review, we discuss the histologic and molecular classifications of TNBC, the genomic alterations these different tumor types harbor, and the potential impact of these alterations on the pathogenesis of these tumors. We also explore the role of the tumor microenvironment in the biology of TNBCs and its potential impact on therapeutic response. Dissecting the biology and understanding the therapeutic dependencies of each TNBC subtype will be essential to delivering on the promise of precision medicine for patients with triple-negative disease.
Topics: Genomics; High-Throughput Nucleotide Sequencing; Humans; Receptors, Estrogen; Triple Negative Breast Neoplasms; Tumor Microenvironment
PubMed: 35073169
DOI: 10.1146/annurev-pathol-042420-093238 -
Advances in Protein Chemistry and... 2019The primary female sex hormones, estrogens, are responsible for the control of functions of the female reproductive system, as well as the development of secondary... (Review)
Review
The primary female sex hormones, estrogens, are responsible for the control of functions of the female reproductive system, as well as the development of secondary sexual characteristics that appear during puberty and sexual maturity. Estrogens exert their actions by binding to specific receptors, the estrogen receptors (ERs), which in turn activate transcriptional processes and/or signaling events that result in the control of gene expression. These actions can be mediated by direct binding of estrogen receptor complexes to specific sequences in gene promoters (genomic effects), or by mechanisms that do not involve direct binding to DNA (non-genomic effects). Whether acting via direct nuclear effects, indirect non-nuclear actions, or a combination of both, the effects of estrogens on gene expression are controlled by highly regulated complex mechanisms. In this chapter, we summarize the knowledge gained in the past 60years since the discovery of the estrogen receptors on the mechanisms governing estrogen-mediated gene expression. We provide an overview of estrogen biosynthesis, and we describe the main mechanisms by which the female sex hormone controls gene transcription in different tissues and cell types. Specifically, we address the molecular events governing regulation of gene expression via the nuclear estrogen receptors (ERα, and ERβ) and the membrane estrogen receptor (GPER1). We also describe mechanisms of cross-talk between signaling cascades activated by both nuclear and membrane estrogen receptors. Finally, we discuss natural compounds that are able to target specific estrogen receptors and their implications for human health and medical therapeutics.
Topics: Animals; Biosynthetic Pathways; Estrogens; Gene Expression Regulation; Humans; Receptors, Estrogen; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 31036290
DOI: 10.1016/bs.apcsb.2019.01.001 -
Frontiers in Endocrinology 2022Estrogen receptors (ERs) regulate multiple complex physiological processes in humans. Abnormal ER signaling may result in various disorders, including reproductive... (Review)
Review
Estrogen receptors (ERs) regulate multiple complex physiological processes in humans. Abnormal ER signaling may result in various disorders, including reproductive system-related disorders (endometriosis, and breast, ovarian, and prostate cancer), bone-related abnormalities, lung cancer, cardiovascular disease, gastrointestinal disease, urogenital tract disease, neurodegenerative disorders, and cutaneous melanoma. ER alpha (ERα), ER beta (ERβ), and novel G-protein-coupled estrogen receptor 1 (GPER1) have been identified as the most prominent ERs. This review provides an overview of ERα, ERβ, and GPER1, as well as their functions in health and disease. Furthermore, the potential clinical applications and challenges are discussed.
Topics: Estrogen Receptor alpha; Estrogen Receptor beta; Female; Humans; Male; Melanoma; Receptors, Estrogen; Skin Neoplasms
PubMed: 36060947
DOI: 10.3389/fendo.2022.839005 -
International Journal of Molecular... Aug 2018
Topics: Gene Expression Regulation; Gene Regulatory Networks; Receptors, Estrogen; Signal Transduction
PubMed: 30200344
DOI: 10.3390/ijms19092591 -
International Journal of Molecular... Apr 2020Endometriosis is a frequent and chronic inflammatory disease with impacts on reproduction, health and quality of life. This disorder is highly estrogen-dependent and the... (Review)
Review
Endometriosis is a frequent and chronic inflammatory disease with impacts on reproduction, health and quality of life. This disorder is highly estrogen-dependent and the purpose of hormonal treatments is to decrease the endogenous ovarian production of estrogens. High estrogen production is a consistently observed endocrine feature of endometriosis. mRNA and protein levels of estrogen receptors (ER) are different between a normal healthy endometrium and ectopic/eutopic endometrial lesions: endometriotic stromal cells express extraordinarily higher ERβ and significantly lower ERα levels compared with endometrial stromal cells. Aberrant epigenetic regulation such as DNA methylation in endometriotic cells is associated with the pathogenesis and development of endometriosis. Although there is a large body of data regarding ERs in endometriosis, our understanding of the roles of ERα and ERβ in the pathogenesis of endometriosis remains incomplete. The goal of this review is to provide an overview of the links between endometriosis, ERs and the recent advances of treatment strategies based on ERs modulation. We will also attempt to summarize the current understanding of the molecular and cellular mechanisms of action of ERs and how this could pave the way to new therapeutic strategies.
Topics: DNA Methylation; Endometrium; Epigenesis, Genetic; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Gene Expression Regulation; Humans; Receptors, Estrogen; Stromal Cells
PubMed: 32316608
DOI: 10.3390/ijms21082815 -
Essays in Biochemistry Dec 2021The female sex hormone estrogen has been ascribed potent neuroprotective properties. It signals by binding and activating estrogen receptors that, depending on receptor... (Review)
Review
The female sex hormone estrogen has been ascribed potent neuroprotective properties. It signals by binding and activating estrogen receptors that, depending on receptor subtype and upstream or downstream effectors, can mediate gene transcription and rapid non-genomic actions. In this way, estrogen receptors in the brain participate in modulating neural differentiation, proliferation, neuroinflammation, cholesterol metabolism, synaptic plasticity, and behavior. Circulating sex hormones decrease in the course of aging, more rapidly at menopause in women, and slower in men. This review will discuss what this drop entails in terms of modulating neuroprotection and resilience in the aging brain downstream of spatiotemporal estrogen receptor alpha (ERα) and beta (ERβ) signaling, as well as in terms of the sex differences observed in Alzheimer's disease (AD) and Parkinson's disease (PD). In addition, controversies related to ER expression in the brain will be discussed. Understanding the spatiotemporal signaling of sex hormones in the brain can lead to more personalized prevention strategies or therapies combating neurodegenerative diseases.
Topics: Aging; Alzheimer Disease; Brain; Female; Humans; Male; Receptors, Estrogen
PubMed: 34623401
DOI: 10.1042/EBC20200162 -
Frontiers in Endocrinology 2022The physiological role of estrogen in the female endometrium is well established. On the basis of responses to steroid hormones (progesterone, androgen, and estrogen),... (Review)
Review
The physiological role of estrogen in the female endometrium is well established. On the basis of responses to steroid hormones (progesterone, androgen, and estrogen), the endometrium is considered to have proliferative and secretory phases. Estrogen can act in the endometrium by interacting with estrogen receptors (ERs) to induce mucosal proliferation during the proliferative phase and progesterone receptor (PR) synthesis, which prepare the endometrium for the secretory phase. Mouse knockout studies have shown that ER expression, including ERα, ERβ, and G-protein-coupled estrogen receptor (GPER) in the endometrium is critical for normal menstrual cycles and subsequent pregnancy. Incorrect expression of ERs can produce many diseases that can cause endometriosis, endometrial hyperplasia (EH), and endometrial cancer (EC), which affect numerous women of reproductive age. ERα promotes uterine cell proliferation and is strongly associated with an increased risk of EC, while ERβ has the opposite effects on ERα function. GPER is highly expressed in abnormal EH, but its expression in EC patients is paradoxical. Effective treatments for endometrium-related diseases depend on understanding the physiological function of ERs; however, much less is known about the signaling pathways through which ERs functions in the normal endometrium or in endometrial diseases. Given the important roles of ERs in the endometrium, we reviewed the published literature to elaborate the regulatory role of estrogen and its nuclear and membrane-associated receptors in maintaining the function of endometrium and to provide references for protecting female reproduction. Additionally, the role of drugs such as tamoxifen, raloxifene, fulvestrant and G-15 in the endometrium are also described. Future studies should focus on evaluating new therapeutic strategies that precisely target specific ERs and their related growth factor signaling pathways.
Topics: Animals; Endometrial Neoplasms; Endometrium; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogens; Female; Humans; Mice; Pregnancy; Receptors, Estrogen; Receptors, G-Protein-Coupled; Uterine Diseases
PubMed: 35295981
DOI: 10.3389/fendo.2022.827724 -
International Journal of Molecular... Jun 2020Cardiovascular Diseases (CVDs) are the leading cause of death globally. More than 17 million people die worldwide from CVD per year. There is considerable evidence... (Review)
Review
Cardiovascular Diseases (CVDs) are the leading cause of death globally. More than 17 million people die worldwide from CVD per year. There is considerable evidence suggesting that estrogen modulates cardiovascular physiology and function in both health and disease, and that it could potentially serve as a cardioprotective agent. The effects of estrogen on cardiovascular function are mediated by nuclear and membrane estrogen receptors (ERs), including estrogen receptor alpha (ERα), estrogen receptor beta (ERβ), and G-protein-coupled ER (GPR30 or GPER). Receptor binding in turn confers pleiotropic effects through both genomic and non-genomic signaling to maintain cardiovascular homeostasis. Each ER has been implicated in multiple pre-clinical cardiovascular disease models. This review will discuss current reports on the underlying molecular mechanisms of the ERs in regulating vascular pathology, with a special emphasis on hypertension, pulmonary hypertension, and atherosclerosis, as well as in regulating cardiac pathology, with a particular emphasis on ischemia/reperfusion injury, heart failure with reduced ejection fraction, and heart failure with preserved ejection fraction.
Topics: Animals; Cardiovascular Diseases; Cardiovascular System; Disease Susceptibility; Gene Expression Regulation; Humans; Receptors, Estrogen; Signal Transduction
PubMed: 32560398
DOI: 10.3390/ijms21124314 -
Biochemia Medica 2014Estrogens have long been known as important regulators of the female reproductive functions; however, our understanding of the role estrogens play in the human body has... (Review)
Review
Estrogens have long been known as important regulators of the female reproductive functions; however, our understanding of the role estrogens play in the human body has changed significantly over the past years. It is now commonly accepted that estrogens and androgens have important functions in both female and male physiology and pathology. This is in part due to the local synthesis and action of estrogens that broadens the role of estrogen signaling beyond that of the endocrine system. Furthermore, there are several different mechanisms through which the three estrogen receptors (ERs), ERα, ERβ and G protein-coupled estrogen receptor 1 (GPER1) are able to regulate target gene transcription. ERα and ERβ are mostly associated with the direct and indirect genomic signaling pathways that result in target gene expression. Membrane-bound GPER1 is on the other hand responsible for the rapid non-genomic actions of estrogens that activate various protein-kinase cascades. Estrogen signaling is also tightly connected with another important regulatory entity, i.e. epigenetic mechanisms. Posttranslational histone modifications, microRNAs (miRNAs) and DNA methylation have been shown to influence gene expression of ERs as well as being regulated by estrogen signaling. Moreover, several coregulators of estrogen signaling also exhibit chromatin-modifying activities further underlining the importance of epigenetic mechanisms in estrogen signaling. This review wishes to highlight the newer aspects of estrogen signaling that exceed its classical endocrine regulatory role, especially emphasizing its tight intertwinement with epigenetic mechanisms.
Topics: Epigenesis, Genetic; Estrogens; Female; Gene Expression Regulation; Humans; Male; Receptors, Estrogen; Signal Transduction; Structure-Activity Relationship; Tissue Distribution
PubMed: 25351351
DOI: 10.11613/BM.2014.035 -
Essays in Biochemistry Dec 2021Estrogen receptor (ER) is a member of the nuclear receptor superfamily whose members share conserved domain structures, including a DNA-binding domain (DBD) and... (Review)
Review
Estrogen receptor (ER) is a member of the nuclear receptor superfamily whose members share conserved domain structures, including a DNA-binding domain (DBD) and ligand-binding domain (LBD). Estrogenic chemicals work as ligands for activation or repression of ER-mediated transcriptional activity derived from two transactivation domains: AF-1 and AF-2. AF-2 is localized in the LBD, and helix 12 of the LBD is essential for controlling AF-2 functionality. The positioning of helix 12 defines the ER alpha (ERα) ligand properties as agonists or antagonists. In contrast, it is still less well defined as to the ligand-dependent regulation of N-terminal AF-1 activity. It has been thought that the action of selective estrogen receptor modulators (SERMs) is mediated by the regulation of a tissue specific AF-1 activity rather than AF-2 activity. However, it is still unclear how SERMs regulate AF-1 activity in a tissue-selective manner. This review presents some recent observations toward information of ERα mediated SERM actions related to the ERα domain functionality, focusing on the following topics. (1) The F-domain, which is connected to helix 12, controls 4-hydroxytamoxifen (4OHT) mediated AF-1 activation associated with the receptor dimerization activity. (2) The zinc-finger property of the DBD for genomic sequence recognition. (3) The novel estrogen responsive genomic DNA element, which contains multiple long-spaced direct-repeats without a palindromic ERE sequence, is differentially recognized by 4OHT and E2 ligand bound ERα transactivation complexes.
Topics: Estrogen Receptor alpha; Ligands; Protein Binding; Receptors, Estrogen; Selective Estrogen Receptor Modulators
PubMed: 34028522
DOI: 10.1042/EBC20200167