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International Journal of Molecular... Oct 2021Lipedema is a painful fat disorder that affects ~11% of the female population. It is characterized by bilateral, disproportionate accumulation of subcutaneous adipose... (Review)
Review
Lipedema is a painful fat disorder that affects ~11% of the female population. It is characterized by bilateral, disproportionate accumulation of subcutaneous adipose tissue predominantly in the lower body. The onset of lipedema pathophysiology is thought to occur during periods of hormonal fluctuation, such as puberty, pregnancy, or menopause. Although the identification and characterization of lipedema have improved, the underlying disease etiology remains to be elucidated. Estrogen, a key regulator of adipocyte lipid and glucose metabolism, and female-associated body fat distribution are postulated to play a contributory role in the pathophysiology of lipedema. Dysregulation of adipose tissue accumulation via estrogen signaling likely occurs by two mechanisms: (1). altered adipocyte estrogen receptor distribution (ERα/ERß ratio) and subsequent metabolic signaling and/or (2). increased release of adipocyte-produced steroidogenic enzymes leading to increased paracrine estrogen release. These alterations could result in increased activation of peroxisome proliferator-activated receptor γ (PPARγ), free fatty acid entry into adipocytes, glucose uptake, and angiogenesis while decreasing lipolysis, mitochondriogenesis, and mitochondrial function. Together, these metabolic alterations would lead to increased adipogenesis and adipocyte lipid deposition, resulting in increased adipose depot mass. This review summarizes research characterizing estrogen-mediated adipose tissue metabolism and its possible relation to excessive adipose tissue accumulation associated with lipedema.
Topics: Adipose Tissue; Animals; Estrogens; Humans; Lipedema; Receptors, Estrogen; Signal Transduction
PubMed: 34769153
DOI: 10.3390/ijms222111720 -
Steroids Nov 2014Estrogen receptors alpha (ERα) and beta (ERβ) are nuclear transcription factors that are involved in the regulation of many complex physiological processes in humans.... (Review)
Review
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.
Topics: Estrogen Receptor alpha; Estrogen Receptor beta; Estrogens; Humans; Models, Chemical; Selective Estrogen Receptor Modulators
PubMed: 24971815
DOI: 10.1016/j.steroids.2014.06.012 -
Frontiers in Endocrinology 2021
Topics: Animals; Endocrine Disruptors; Humans; Receptors, Estrogen; Receptors, G-Protein-Coupled; Sex Characteristics
PubMed: 34912301
DOI: 10.3389/fendo.2021.794344 -
Frontiers in Endocrinology 2021
Topics: Animals; Autoimmune Diseases; Humans; Neoplasms; Receptors, Estrogen; Receptors, G-Protein-Coupled
PubMed: 34858355
DOI: 10.3389/fendo.2021.794332 -
Cold Spring Harbor Protocols Mar 2015The strategy of fusing a protein of interest to a hormone-binding domain (HBD) of a steroid hormone receptor allows fine control of the activity of the fused protein....
The strategy of fusing a protein of interest to a hormone-binding domain (HBD) of a steroid hormone receptor allows fine control of the activity of the fused protein. Such fusion proteins are inactive in the absence of ligand, because they are complexed with a variety of intracellular polypeptides. Upon ligand binding, the receptor is released from its inhibitory complex and the fusion protein becomes functional. In the murine estrogen receptor (ER) fusion system, proteins are fused to the HBD of the ER. The system relies on the use of a mutant ER known as ER(TAM). Compared to the wild-type HBD, ER(TAM) has 1000-fold lower affinity for estrogen, yet remains responsive to activation by the synthetic steroid 4-hydroxytamoxifen (4-OHT). Because 4-OHT is expensive, animals can be treated with the cheaper precursor tamoxifen, which is converted into 4-OHT by a liver enzyme. Here we present an overview of the methods used to deliver tamoxifen to mice. The most used method is intraperitoneal injection, because the amount of administered compound can be better controlled, but delivery by oral gavage is also possible. For short-term and immediate-effect studies or when conversion of tamoxifen by the liver is to be avoided, 4-OHT can be used directly.
Topics: Administration, Oral; Animals; Gene Expression Regulation; Injections, Intraperitoneal; Mice; Receptors, Estrogen; Recombinant Fusion Proteins; Selective Estrogen Receptor Modulators; Tamoxifen
PubMed: 25734062
DOI: 10.1101/pdb.prot077966 -
Molecular Metabolism Sep 2018In addition to their crucial role in reproduction, estrogens are key regulators of energy and glucose homeostasis and they also exert several cardiovascular protective... (Review)
Review
BACKGROUND
In addition to their crucial role in reproduction, estrogens are key regulators of energy and glucose homeostasis and they also exert several cardiovascular protective effects. These beneficial actions are mainly mediated by estrogen receptor alpha (ERα), which is widely expressed in metabolic and vascular tissues. As a member of the nuclear receptor superfamily, ERα was primarily considered as a transcription factor that controls gene expression through the activation of its two activation functions (ERαAF-1 and ERαAF-2). However, besides these nuclear actions, a pool of ERα is localized in the vicinity of the plasma membrane, where it mediates rapid signaling effects called membrane-initiated steroid signals (MISS) that have been well described in vitro, especially in endothelial cells.
SCOPE OF THE REVIEW
This review aims to summarize our current knowledge of the mechanisms of nuclear vs membrane ERα activation that contribute to the cardiometabolic protection conferred by estrogens. Indeed, new transgenic mouse models (affecting either DNA binding, activation functions or membrane localization), together with the use of novel pharmacological tools that electively activate membrane ERα effects recently allowed to begin to unravel the different modes of ERα signaling in vivo.
CONCLUSION
Altogether, available data demonstrate the prominent role of ERα nuclear effects, and, more specifically, of ERαAF-2, in the preventive effects of estrogens against obesity, diabetes, and atheroma. However, membrane ERα signaling selectively mediates some of the estrogen endothelial/vascular effects (NO release, reendothelialization) and could also contribute to the regulation of energy balance, insulin sensitivity, and glucose metabolism. Such a dissection of ERα biological functions related to its subcellular localization will help to understand the mechanism of action of "old" ER modulators and to design new ones with an optimized benefit/risk profile.
Topics: Active Transport, Cell Nucleus; Animals; Cell Nucleus; Estrogens; Humans; Myocytes, Cardiac; Receptors, Estrogen; Signal Transduction
PubMed: 29807870
DOI: 10.1016/j.molmet.2018.05.009 -
Cells Feb 2021Female infertility is mainly caused by ovulation disorders, which affect female reproduction and pregnancy worldwide, with polycystic ovary syndrome (PCOS) being the... (Review)
Review
Female infertility is mainly caused by ovulation disorders, which affect female reproduction and pregnancy worldwide, with polycystic ovary syndrome (PCOS) being the most prevalent of these. PCOS is a frequent endocrine disease that is associated with abnormal function of the female sex hormone estrogen and estrogen receptors (ERs). Estrogens mediate genomic effects through ERα and ERβ in target tissues. The G-protein-coupled estrogen receptor (GPER) has recently been described as mediating the non-genomic signaling of estrogen. Changes in estrogen receptor signaling pathways affect cellular activities, such as ovulation; cell cycle phase; and cell proliferation, migration, and invasion. Over the years, some selective estrogen receptor modulators (SERMs) have made substantial strides in clinical applications for subfertility with PCOS, such as tamoxifen and clomiphene, however the role of ER in PCOS still needs to be understood. This article focuses on the recent progress in PCOS caused by the abnormal expression of estrogen and ERs in the ovaries and uterus, and the clinical application of related targeted small-molecule drugs.
Topics: Endometrium; Estrogen Receptor Modulators; Female; Humans; Models, Biological; Ovulation; Polycystic Ovary Syndrome; Receptors, Estrogen
PubMed: 33669960
DOI: 10.3390/cells10020459 -
International Journal of Molecular... Jan 2022It is known that estrogen stimulates growth and inhibits apoptosis through estrogen receptor(ER)-mediated mechanisms in many cancer cell types. Interestingly, there is... (Review)
Review
It is known that estrogen stimulates growth and inhibits apoptosis through estrogen receptor(ER)-mediated mechanisms in many cancer cell types. Interestingly, there is strong evidence that estrogens can also induce apoptosis, activating different ER isoforms in cancer cells. It has been observed that E2/ERα complex activates multiple pathways involved in both cell cycle progression and apoptotic cascade prevention, while E2/ERβ complex in many cases directs the cells to apoptosis. However, the exact mechanism of estrogen-induced tumor regression is not completely known. Nevertheless, ERs expression levels of specific splice variants and their cellular localization differentially affect outcome of estrogen-dependent tumors. The goal of this review is to provide a general overview of current knowledge on ERs-mediated apoptosis that occurs in main hormone dependent-cancers. Understanding the molecular mechanisms underlying the induction of ER-mediated cell death will be useful for the development of specific ligands capable of triggering apoptosis to counteract estrogen-dependent tumor growth.
Topics: Animals; Apoptosis; Humans; Neoplasms, Hormone-Dependent; Receptors, Estrogen; Signal Transduction
PubMed: 35163166
DOI: 10.3390/ijms23031242 -
Cells Oct 2020Triple-negative breast cancer (TNBC) lacks estrogen receptor (ER) α, but the expression of estrogen receptors ERβ and G protein-coupled estrogen receptor 1 (GPER-1) is... (Review)
Review
Triple-negative breast cancer (TNBC) lacks estrogen receptor (ER) α, but the expression of estrogen receptors ERβ and G protein-coupled estrogen receptor 1 (GPER-1) is able to trigger estrogen-responsivity in TNBC. Estrogen signaling in TNBC can also be activated and modulated by the constitutively active estrogen-related receptors (ERRs). In this review article, we discuss the role of ERβ and GPER-1 as mediators of E2 action in TNBC as well as the function of ERRs as activators and modulators of estrogen signaling in this cancer entity. For this purpose, original research articles on estrogen actions in TNBC were considered, which are listed in the PubMed database. Additionally, we performed meta-analyses of publicly accessible integrated gene expression and survival data to elucidate the association of ERβ, GPER-1, and ERR expression levels in TNBC with survival. Finally, options for endocrine therapy strategies for TNBC were discussed.
Topics: Estrogens; Humans; Kaplan-Meier Estimate; Models, Biological; Receptors, Estrogen; Signal Transduction; Triple Negative Breast Neoplasms
PubMed: 33114740
DOI: 10.3390/cells9112358 -
American Society of Clinical Oncology... Jun 2023We review key topics in the management of estrogen receptor (ER)-positive human epidermal growth factor receptor 2-negative breast cancer. The single biggest challenge... (Review)
Review
We review key topics in the management of estrogen receptor (ER)-positive human epidermal growth factor receptor 2-negative breast cancer. The single biggest challenge in management of this disease is late relapse, and we review new methods for identifying which patients are at risk of late relapse and potential therapeutic approaches in clinical trials. CDK4/6 inhibitors have become a standard treatment option for high-risk patients in both the adjuvant setting and the first-line metastatic setting, and we review data on optimal treatment after progression on CDK4/6 inhibitors. Targeting the estrogen receptor remains the single most effective way of targeting the cancer, and we review the developments in new oral selective ER degraders that are becoming a standard of care in cancers with ESR1 mutations and potential future directions.
Topics: Humans; Female; Breast Neoplasms; Receptors, Estrogen; Drug Resistance, Neoplasm; Recurrence; Estrogen Receptor alpha
PubMed: 37319380
DOI: 10.1200/EDBK_390922