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Cells
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Estrogen Receptor Expression and Function in Health and Disease
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Estrogen Receptor Expression and Function in Health and Disease

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (1 September 2019) | Viewed by 38771

Special Issue Editor

Dr. Elena Ortona

E-Mail Website
Guest Editor
Center for Gender Specific Medicine, Istituto Superiore di Sanità, Rome, Italy
Interests: immunity; cancer; autoimmune diseases; estrogens; gender differences

Special Issue Information

Dear Colleagues,

The involvement of estrogens, which influence many physiologic processes, has been shown in the development or progression of several diseases, including some cancers, cardiovascular diseases, and autoimmune disorders. Estrogenic signal is transferred via estrogen receptors (ER), which have dual localization, predominantly intracellular, but also in plasma membrane. The primary mechanism of estrogen activity is mediated by transcriptional actions of the intracellular, nuclear estrogen receptors, ERα and ERβ, to produce genomic effects. It is known that ERα and ERβ are encoded by separate genes (ESR1 and ESR2, respectively) and are distinct in their tissue expression patterns and functions, although they both belong to one superfamily of nuclear receptors. Numerous mRNA splice variants exist for both ERα and ERβ, although their exact function in physiology and human diseases remains to be elucidated. At least three ERα (at 66, 46, and 36 kDa) isoforms and five ERβ (ranging from 53 to 59 kDa) isoforms have been identified. ERα and ERβ function as ligand-dependent transcription factors that directly bind to specific estrogen responsive elements, thus regulating the transcription of E2-sensitive genes. ERβ can trans-activate transcription only when a heterodimer with the functional ERβ1 receptor of 59 kDa is formed. In addition, ERα and ERβ, without direct binding to DNA, regulate transcription indirectly by binding to other transcription factors. A variety of cellular responses to physiological concentrations of E2 occur rapidly, within seconds to a few minutes, so that they cannot be mediated by transcription and protein synthesis. These rapid estrogen-mediated effects (referred to as “nongenomic”) are triggered through the activation of non-nuclear membrane-associated ER (mER). Membrane ER have been demonstrated to be localized to plasma membrane lipid rafts; palmitoylation has been demonstrated to promote ER association with caveolins that are necessary transporters of ER to plasma membrane lipid rafts. These receptors are structurally similar to their intracellular counterparts and, after ligand binding, they activate various protein kinase cascades, including extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK), protein kinase A, protein kinase C, Akt, and phosphatidylinositol 3-OH kinase (PI3K).

Dr. Elena Ortona
Guest Editor

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Keywords

  • estrogen receptor
  • apoptosis
  • autophagy
  • cell signaling
  • pathogenesis

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Published Papers (5 papers)

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Research

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17 pages, 1605 KiB  
Article
Late Onset of Estrogen Therapy Impairs Carotid Function of Senescent Females in Association with Altered Prostanoid Balance and Upregulation of the Variant ERα36
by Tiago Januário Costa, Francesc Jiménez-Altayó, Cinthya Echem, Eliana Hiromi Akamine, Rita Tostes, Elisabet Vila, Ana Paula Dantas and Maria Helena Catelli de Carvalho
Cells 2019, 8(10), 1217; https://doi.org/10.3390/cells8101217 - 8 Oct 2019
Cited by 9 | Viewed by 3125
Abstract
Recent analysis of clinical trials on estrogen therapy proposes the existence of a therapeutic window of opportunity for the cardiovascular benefits of estrogens, which depend on women’s age and the onset of therapy initiation. In this study, we aimed to determine how vascular [...] Read more.
Recent analysis of clinical trials on estrogen therapy proposes the existence of a therapeutic window of opportunity for the cardiovascular benefits of estrogens, which depend on women’s age and the onset of therapy initiation. In this study, we aimed to determine how vascular senescence and the onset of estrogen treatment influence the common carotid artery (CCA) function in senescent and non-senescent females. Ovariectomized female senescence-accelerated (SAMP8) or non-senescent (SAMR1) mice were treated with vehicle (OVX) or 17β-estradiol starting at the day of ovariectomy (early-onset, E2E) or 45 days after surgery (late-onset, E2L). In SAMR1, both treatments, E2E and E2L, reduced constriction to phenylephrine (Phe) in CCA [(AUC) OVX: 193.8 ± 15.5; E2E: 128.1 ± 11.6; E2L: 130.2 ± 15.8, p = 0.004] in association with positive regulation of NO/O2- ratio and increased prostacyclin production. In contrast, E2E treatment did not modify vasoconstrictor responses to Phe in OVX-SAMP8 and, yet, E2L increased Phe vasoconstriction [(AUC) OVX: 165.3 ± 10; E2E: 183.3 ± 11.1; E2L: 256.3 ± 30.4, p = 0.005]. Increased vasoconstriction in E2L-SAMP8 was associated with augmented thromboxane A2 and reduced NO production. Analysis of wild-type receptor alpha (ERα66) expression and its variants revealed an increased expression of ERα36 in E2L-SAMP8 in correlation with unfavorable effects of estrogen in those animals. In conclusion, estrogen exerts beneficial effects in non-senescent CCA, regardless of the initiation of the therapy. In senescent CCA, however, estrogen loses its beneficial action even when administered shortly after ovariectomy and may become detrimental when given late after ovariectomy. Aging and onset of estrogen treatment are two critical factors in the mechanism of action of this hormone in CCA. Full article
(This article belongs to the Special Issue Estrogen Receptor Expression and Function in Health and Disease)
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20 pages, 5076 KiB  
Article
17β-Estradiol Modulates SIRT1 and Halts Oxidative Stress-Mediated Cognitive Impairment in a Male Aging Mouse Model
by Mehtab Khan, Rahat Ullah, Shafiq Ur Rehman, Shahid Ali Shah, Kamran Saeed, Tahir Muhammad, Hyun Young Park, Myeung Hoon Jo, Kyonghwan Choe, Bart P.F. Rutten and Myeong Ok Kim
Cells 2019, 8(8), 928; https://doi.org/10.3390/cells8080928 - 19 Aug 2019
Cited by 77 | Viewed by 6819
Abstract
Oxidative stress has been considered the main mediator in neurodegenerative disease and in normal aging processes. Several studies have reported that the accumulation of reactive oxygen species (ROS), elevated oxidative stress, and neuroinflammation result in cellular malfunction. These conditions lead to neuronal cell [...] Read more.
Oxidative stress has been considered the main mediator in neurodegenerative disease and in normal aging processes. Several studies have reported that the accumulation of reactive oxygen species (ROS), elevated oxidative stress, and neuroinflammation result in cellular malfunction. These conditions lead to neuronal cell death in aging-related neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease. Chronic administration of d-galactose (d-gal) for a period of 10 weeks causes ROS generation and neuroinflammation, ultimately leading to cognitive impairment. In this study, we evaluated the estrogen receptor α (ERα)/silent mating type information regulation 2 homolog 1 (SIRT1)-dependent antioxidant efficacy of 17β-estradiol against d-gal-induced oxidative damage-mediated cognitive dysfunction in a male mouse model. The results indicate that 17β-estradiol, by stimulating ERα/SIRT1, halts d-gal-induced oxidative stress–mediated JNK/NF-ҡB overexpression, neuroinflammation and neuronal apoptosis. Moreover, 17β-estradiol ameliorated d-gal-induced AD-like pathophysiology, synaptic dysfunction and memory impairment in adult mouse brains. Interestingly, inhibition of SIRT1 with Ex527 (a potent and selective SIRT1 inhibitor) further enhanced d-gal-induced toxicity and abolished the beneficial effect of 17β-estradiol. Most importantly, for the first time, our molecular docking study reveals that 17β-estradiol allosterically increases the expression of SIRT1 and abolishes the inhibitory potential of d-ga. In summary, we can conclude that 17β-estradiol, in an ERα/SIRT1-dependent manner, abrogates d-gal-induced oxidative stress–mediated memory impairment, neuroinflammation, and neurodegeneration in adult mice. Full article
(This article belongs to the Special Issue Estrogen Receptor Expression and Function in Health and Disease)
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Review

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13 pages, 624 KiB  
Review
Estrogen Receptors and Melanoma: A Review
by Emi Dika, Annalisa Patrizi, Martina Lambertini, Nicholas Manuelpillai, Michelangelo Fiorentino, Annalisa Altimari, Manuela Ferracin, Mattia Lauriola, Enrica Fabbri, Elena Campione, Giulia Veronesi and Federica Scarfì
Cells 2019, 8(11), 1463; https://doi.org/10.3390/cells8111463 - 19 Nov 2019
Cited by 49 | Viewed by 6836
Abstract
In the last three decades cutaneous melanoma has been widely investigated as a steroid hormone-sensitive cancer. Following this hypothesis, many epidemiological studies have investigated the relationship between estrogens and melanoma. No evidence to date has supported this association due to the great complexity [...] Read more.
In the last three decades cutaneous melanoma has been widely investigated as a steroid hormone-sensitive cancer. Following this hypothesis, many epidemiological studies have investigated the relationship between estrogens and melanoma. No evidence to date has supported this association due to the great complexity of genetic, external and environmental factors underlying the development of this cancer. Molecular mechanisms through which estrogen and their receptor exert a role in melanoma genesis are still under investigation with new studies increasingly focusing on the discovery of new molecular targets for therapeutic treatments. Full article
(This article belongs to the Special Issue Estrogen Receptor Expression and Function in Health and Disease)
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15 pages, 934 KiB  
Review
Estrogen-Receptor Expression and Function in Female Reproductive Disease
by Zi-Run Tang, Rui Zhang, Zheng-Xing Lian, Shou-Long Deng and Kun Yu
Cells 2019, 8(10), 1123; https://doi.org/10.3390/cells8101123 - 21 Sep 2019
Cited by 155 | Viewed by 17108
Abstract
Estrogen receptors (ER) include ER alpha, ER beta and new membrane receptor G protein-coupled receptor 30 (GPR30). Estrogen receptors are key receptors to maintain ovarian granulosa cell differentiation, follicle and oocyte growth and development, and ovulation function. The abnormal functions of estrogen, its [...] Read more.
Estrogen receptors (ER) include ER alpha, ER beta and new membrane receptor G protein-coupled receptor 30 (GPR30). Estrogen receptors are key receptors to maintain ovarian granulosa cell differentiation, follicle and oocyte growth and development, and ovulation function. The abnormal functions of estrogen, its receptors, and estradiol synthesis-related enzymes are closely related to clinical reproductive endocrine diseases, such as polycystic ovary syndrome (PCOS) and endometriosis (EMS). At present, hormone therapy is the main treatment for ovarian-related diseases, and a stable hormone environment is established by regulating ovarian function. In recent years, some estrogen-related drugs have made great progress, such as clomiphene, which is a nonsteroidal antiestrogen drug in clinical application. This article elaborates on the regulatory role of estrogen and its nuclear receptors and membrane receptors in oocyte development, especially female reproductive diseases related to the abnormal expression of estrogen and its receptors. We also highlighted the latest advances of treatment strategy for these diseases and the application of related targeted small molecule drugs in clinical research and treatment, so as to provide reference for the treatment of female reproductive diseases. Full article
(This article belongs to the Special Issue Estrogen Receptor Expression and Function in Health and Disease)
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Other

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14 pages, 3956 KiB  
Brief Report
Autoantibodies Specific to ERα are Involved in Tamoxifen Resistance in Hormone Receptor Positive Breast Cancer
by Angela Maselli, Stefania Parlato, Rossella Puglisi, Carla Raggi, Massimo Spada, Daniele Macchia, Giada Pontecorvi, Elisabetta Iessi, Maria Teresa Pagano, Francesca Cirulli, Lucia Gabriele, Alessandra Carè, Patrizia Vici, Laura Pizzuti, Maddalena Barba, Paola Matarrese, Marina Pierdominici and Elena Ortona
Cells 2019, 8(7), 750; https://doi.org/10.3390/cells8070750 - 19 Jul 2019
Cited by 9 | Viewed by 4204
Abstract
Tamoxifen resistance is a major hurdle in the treatment of estrogen receptor (ER)-positive breast cancer. The mechanisms of tamoxifen resistance are not fully understood although several underlying molecular events have been suggested. Recently, we identified autoantibodies reacting with membrane-associated ERα (anti-ERα Abs) in [...] Read more.
Tamoxifen resistance is a major hurdle in the treatment of estrogen receptor (ER)-positive breast cancer. The mechanisms of tamoxifen resistance are not fully understood although several underlying molecular events have been suggested. Recently, we identified autoantibodies reacting with membrane-associated ERα (anti-ERα Abs) in sera of breast cancer patients, able to promote tumor growth. Here, we investigated whether anti-ERα Abs purified from sera of ER-positive breast cancer patients could contribute to tamoxifen resistance. Anti-ERα Abs inhibited tamoxifen-mediated effects on cell cycle and proliferation in MCF-7 cells. Moreover, anti-ERα Abs hampered the tamoxifen-mediated reduction of tumor growth in SCID mice xenografted with breast tumor. Notably, simvastatin-mediated disaggregation of lipid rafts, where membrane-associated ERα is embedded, restored tamoxifen sensitivity, preventing anti-ERα Abs effects. In conclusion, detection of serum anti-ERα Abs may help predict tamoxifen resistance and concur to appropriately inform therapeutic decisions concerning hormone therapy in ER-positive breast cancer patients. Full article
(This article belongs to the Special Issue Estrogen Receptor Expression and Function in Health and Disease)
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