Role of estrogen receptors in health and disease

Chen, Peng; Li, Bo; Ouyang, Liang

doi:10.3389/fendo.2022.839005

Cited by 94 publications

(68 citation statements)

References 295 publications

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“…ERβ is involved in various diseases and different cancer types of the reproductive tract, as well as in other non-reproductive diseases, such as malignancies of the gastrointestinal tract [ 25 , 26 ]. Although not necessarily transferable to humans, mouse knockout models are a valuable tool to clarify the role of ERβ in health and disease [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

“…Extensive studies have been performed on the role of estrogen receptors in health and disease. ERβ is involved in various malignancies of the reproductive tract, such as endometriosis, breast, ovarian or prostate cancer [ 25 , 26 ]. Studies showed that not only healthy granulosa cells in the ovary express ERβ, but it is expressed also in cells that had transformed from normal proliferating cells to tumor cells.…”

Section: Introductionmentioning

confidence: 99%

“…Consequently, one therapeutic option for ovarian granulosa cell tumors besides chemotherapy and surgery is the usage of anti-hormonal therapies with, for instance, aromatase inhibitors [ 29 ], which however, strongly depend on the hormone receptor status of the tumor [ 30 ]. Besides its role in disease of the reproductive tract, ERβ has also multifaceted roles in the pathogenesis of diseases of the non-reproductive system including in esophageal diseases or gastric cancers [ 25 , 26 ]. However, there is still ambiguity regarding the distribution and detection of these, especially in rodent tissues.…”

Section: Introductionmentioning

confidence: 99%

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Immunohistochemical Detection of Estrogen Receptor-Beta (ERβ) with PPZ0506 Antibody in Murine Tissue: From Pitfalls to Optimization

et al. 2022

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The estrogen receptor beta (ERβ) is physiologically essential for reproductive biology and is implicated in various diseases. However, despite more than 20 years of intensive research on ERβ, there are still uncertainties about its distribution in tissues and cellular expression. Several studies show contrasts between mRNA and protein levels, and the use of knockout strategies revealed that many commercially available antibodies gave false-positive expression results. Recently, a specific monoclonal antibody against human ERβ (PPZ0506) showed cross-reactivity with rodents and was optimized for the detection of rat ERβ. Herein, we established an immunohistochemical detection protocol for ERβ protein in mouse tissue. Staining was optimized on murine ovaries, as granulosa cells are known to strongly express ERβ. The staining results were confirmed by western blot analysis and RT-PCR. To obtain accurate and reliable staining results, different staining conditions were tested in paraffin-embedded tissues. Different pitfalls were encountered in immunohistochemical detection. Strong heat-induced epitope retrieval (HIER) and appropriate antibody dilution were required to visualize specific nuclear expression of ERβ. Finally, the specificity of the antibody was confirmed by using ovaries from Esr2-depleted mice. However, in some animals, strong (non-specific) background staining appeared. These signals could not be significantly alleviated with commercially available additional blocking solutions and are most likely due to estrus-dependent expression of endogenous immunoglobulins. In summary, our study showed that the antibody PPZ0506, originally directed against human ERβ, is also suitable for reliable detection of murine ERβ. An established staining protocol mitigated ambiguities regarding the expression and distribution of ERβ in different tissues and will contribute to an improved understanding of its role and functions in murine tissues in the future.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Immunohistochemical Detection of Estrogen Receptor-Beta (ERβ) with PPZ0506 Antibody in Murine Tissue: From Pitfalls to Optimization

et al. 2022

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“…In pain modulation, estrogen exerts its biological action by binding to estrogen receptors (ERs) at the gene regulation level ( Chen et al, 2022 ). ERα and ERβ have been detected in the spinal cord ( Chen et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Estrogen receptor β/substance P signaling in spinal cord mediates antinociceptive effect in a mouse model of discogenic low back pain

Song

Jin

et al. 2023

Front. Cell. Neurosci.

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IntroductionDiscogenic low back pain (DLBP) is the most commonly described form of back pain. Our previous studies indicated that estrogen-dependent DLBP mechanism was mediated by estrogen receptors (ERs) in the intervertebral disc (IVD) tissue, and the IVD degeneration degree is accompanied by downregulation of ERs, particularly ERβ. However, the neuropathological mechanisms underlying ERs modulation of DLBP are still not well understood. In this study, we investigated the antinociceptive effects of selective ERβ agonists on DLBP-related behavior by regulating substance P in spinal cord and dorsal root ganglia.MethodsTwo weeks after ovariectomies, 18-week-old female mice were randomly separated into four groups: control group; DLBP sham surgery plus vehicle group; DLBP plus vehicle group; DLBP plus ERβ-specific agonist diarylpropionitrile (DPN) group. Behavioral data was collected including behavioral measures of axial back pain (grip force and tail suspension tests) and radiating hypersensitivity (mechanical sensitivity and cold sensitivity test). Dual label scanning confocal immunofluorescence microscopy was used to observe spatial colocalization of ERβ and substance P in spinal cord. Substance P changes in spinal cord and dorsal root ganglia were measured by immunohistochemistry and real-time PCR.ResultsERβ activation could improve both axial and radiating behavioral disorders of DLBP. DPN facilitated the decrease of the amount of time in immobility 1 week after agonist administration. At the time point of 3 weeks, DPN group spent significantly less time in immobility than the vehicle group. In the grip strength tests, starting from postoperative week 1-week 3, DPN injection DLBP mice showed more resistance to stretch than the vehicle injection DLBP mice. Significant differences of cold withdrawal latency time were observed between the DLBP plus DPN injection and DLBP vehicle injection groups at 2- and 3-week injection time point. DPN significantly reversed the paw withdrawal threshold of DLBP mice at the time point of 1, 2, and 3 weeks. Substance P colocalized with ERβ in spinal dorsal horn, mainly in laminae I and II, a connection site of pain transmission. Substance P levels in dorsal horn and dorsal root ganglia of DLBP group were distinctly increased compared with that of control and DLBP sham group. DPN therapy could decrease substance P content in the dorsal horn and the dorsal root ganglia of DLBP mice compared with that of vehicle-treated DLBP mice.DiscussionActivation of ERβ is antinociceptive in the DLBP model by controlling substance P in spinal cord and dorsal root ganglia, which might provide a therapeutic target to manage DLBP in the clinic.

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“…Steroid receptors modulate suites of physiological mechanisms, such as homeostatic functions, growth and development, cellular signaling, sexual differentiation and reproduction, as well as behavior (Szego et al 2003; Whirledge and Cidlowski, 2019). Steroid receptors consist of five major groups: 1) the androgen receptors (ARs), 2) estrogen receptors (ERs), and 3) progesterone receptors (PRs), which mediate the actions of androgens (e.g., testosterone, dihydrotestosterone, and 11-ketotestosterone), estrogens (e.g., estradiol), and progestins (e.g., progesterone) on the development and maintenance of the reproductive, musculoskeletal, cardiovascular, immune, and central nervous systems (reviewed in Brinton et al, 2008; Chen et al, 2022; Davey and Grossmann, 2016; Mani et al 1997), and 4) the glucocorticoid receptors (GRs) and 5) mineralocorticoid receptors (MRs), which facilitate the actions of glucocorticoids (e.g., cortisol) and mineralocorticoids (e.g., aldosterone) on metabolism, growth and development, cardiovascular function, ion transport, and salt balance (reviewed in Pascual-Le Tallec and Lombés, 2005; Timmermans et al, 2019). Prior work suggests that extant steroid receptors evolved from an ancestral estrogen receptor that had estrogen-like functionality and preceded the origin of bilaterally symmetric animals, followed by an ancestral progesterone receptor (Thornton, 2001; Thornton et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

A phylogenetics-based nomenclature system for steroid receptors in teleost fishes

Hoadley

Munley

Alward

2022

Preprint

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Teleost fishes have emerged as tractable models for studying the neuroendocrine regulation of social behavior via molecular genetic techniques, such as CRISPR/Cas9 gene editing. Moreover, teleosts provide an opportunity to investigate the evolution of steroid receptors and their functions, as species within this lineage possess novel steroid receptor paralogs that resulted from a teleost-specific whole genome duplication. Although teleost fishes have grown in popularity as models for behavioral neuroendocrinology, there is not a consistent nomenclature system for steroid receptors and their genes, which may impede a clear understanding of steroid receptor paralogs and their functions. Here, we used a phylogenetic approach to assess the relatedness of protein sequences encoding steroid receptor paralogs in 18 species from 12 different orders of the Infraclass Teleostei. While most similarly named sequences grouped based on the established phylogeny of the teleost fish lineage, our analysis revealed several inconsistencies in the nomenclature of steroid receptor paralogs, particularly for sequences encoding estrogen receptor beta (ERβ) and estrogen-related receptor gamma (ERγ). Based on our results, we propose a nomenclature system for teleosts in which Greek symbols refer to proteins and numbers refer to genes encoding different subtypes of steroid receptors within the five major groups of this nuclear receptor subfamily. Collectively, our results bridge a critical gap by providing a cohesive naming system for steroid receptors in teleost fishes, which will serve to improve communication, promote collaboration, and enhance our understanding of the evolution and function of steroid receptors across vertebrates.

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Role of estrogen receptors in health and disease

Cited by 94 publications

References 295 publications

Immunohistochemical Detection of Estrogen Receptor-Beta (ERβ) with PPZ0506 Antibody in Murine Tissue: From Pitfalls to Optimization

Immunohistochemical Detection of Estrogen Receptor-Beta (ERβ) with PPZ0506 Antibody in Murine Tissue: From Pitfalls to Optimization

Estrogen receptor β/substance P signaling in spinal cord mediates antinociceptive effect in a mouse model of discogenic low back pain

A phylogenetics-based nomenclature system for steroid receptors in teleost fishes

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