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Steroid hormone receptor

Steroid hormone receptors (SHRs) are a subclass of nuclear receptors that function as ligand-activated transcription factors, binding steroid hormones such as estrogens, androgens, progestogens, glucocorticoids, and mineralocorticoids to regulate gene expression and mediate diverse physiological processes including reproduction, metabolism, inflammation, and stress responses.^[1] The discovery of steroid hormone receptors dates back to the mid-20th century. In 1958, Elwood V. Jensen identified the estrogen receptor using radiolabeled estradiol, revealing specific high-affinity binding in target tissues such as the uterus. This work laid the foundation for understanding hormone-receptor interactions. In 1963, Peter Karlson proposed the "hormone-gene" hypothesis, positing that steroid hormones exert their effects by binding intracellular receptors that modulate gene transcription. These foundational insights spurred further research into the nuclear receptor superfamily.^[2]^[3] These receptors, comprising six classical members in humans (e.g., estrogen receptors α and β, progesterone receptor, androgen receptor, glucocorticoid receptor, mineralocorticoid receptor), translate endocrine signals into transcriptional outcomes by interacting with DNA and coregulatory proteins.^[4] Structurally, SHRs exhibit a modular organization with four main domains: an N-terminal domain (NTD) containing the ligand-independent activation function 1 (AF-1), which is often intrinsically disordered to enable dynamic protein interactions; a central DNA-binding domain (DBD) featuring two zinc finger motifs for sequence-specific DNA recognition; a flexible hinge region that undergoes post-translational modifications; and a C-terminal ligand-binding domain (LBD) housing the ligand-dependent activation function 2 (AF-2) and a hydrophobic pocket for hormone binding.^[5] Upon ligand binding, SHRs dissociate from inhibitory heat shock proteins, dimerize, translocate to the nucleus, and bind to hormone response elements (HREs) such as estrogen response elements (EREs) or glucocorticoid response elements (GREs), thereby recruiting coactivators to initiate chromatin remodeling and RNA polymerase II-mediated transcription.^[6] In addition to this classical genomic pathway, SHRs can elicit rapid non-genomic effects through membrane localization, activating signaling cascades like MAPK/ERK or PI3K/Akt to influence cell proliferation and survival.^[5] Dysregulation of SHR signaling is implicated in numerous pathologies, including hormone-dependent cancers (e.g., breast, prostate), metabolic disorders, and autoimmune diseases, making these receptors key therapeutic targets for selective modulators like tamoxifen or dexamethasone.^[5] The synergistic action of AF-1 and AF-2 domains, modulated by phosphorylation and coregulator exchange, underscores the context-dependent nature of SHR activity across cell types and physiological states.^[6]

Introduction

Definition

Steroid hormones are a class of lipophilic signaling molecules derived from cholesterol that readily diffuse across cell membranes due to their nonpolar structure.^[7] These hormones encompass estrogens, androgens, glucocorticoids, mineralocorticoids, and progestogens, each regulating diverse physiological processes such as reproduction, metabolism, and stress responses.^[8] Steroid hormone receptors are intracellular or membrane-associated proteins that specifically bind these steroid hormones with high affinity, typically in the nanomolar range, to initiate cellular signaling.^[9] Upon ligand binding, these receptors undergo conformational changes that enable them to modulate target gene expression or activate rapid signaling pathways.^[10] The receptors are primarily classified into classical nuclear receptors, which function as intracellular ligand-activated transcription factors, and non-classical receptors, which are often membrane-associated and mediate rapid, non-genomic actions.^[11] Steroid hormone receptors belong to the nuclear receptor superfamily, specifically the NR3C subfamily (with estrogen receptors in the related NR3A group), which comprises 48 members in humans, though only select ones—such as ESR1/2 (estrogen), AR (androgen), GR (glucocorticoid), PR (progesterone), and MR (mineralocorticoid)—bind steroid hormones.^[12]

Historical background

The discovery of steroid hormones and their physiological effects began in the early 20th century, with key isolations marking initial observations of their roles in reproduction and development. Estrogen was first isolated in 1929 from the urine of pregnant women, enabling studies on its influence on female reproductive tissues.^[13] Progesterone followed in 1934, extracted from corpora lutea by Willard M. Allen and George W. Corner, revealing its essential function in maintaining pregnancy.^[14] These milestones, along with characterizations by Adolf Butenandt, Tadeus Reichstein, and Edward Doisy in the 1920s and 1930s, laid the groundwork for understanding steroid hormone actions. Butenandt shared the 1939 Nobel Prize in Chemistry with Leopold Ruzicka for their work on sex hormones.^[15] In the mid-20th century, the concept of specific receptor proteins mediating steroid effects emerged through pioneering biochemical experiments. In 1958, Elwood V. Jensen used tritium-labeled estradiol to demonstrate high-affinity binding in target tissues like the uterus, identifying the first steroid hormone receptor—the estrogen receptor—in mammals.^[2] This radiolabeling approach revolutionized receptor detection, confirming that steroids concentrate in responsive cells via saturable, specific proteins. Building on this, Peter Karlson proposed the "hormone-gene" hypothesis in 1963, positing that steroid hormones directly regulate gene transcription through intracellular receptors, shifting paradigms from metabolic to genomic actions.^[3] Throughout the 1960s and 1970s, similar receptors for progesterone, glucocorticoids, and androgens were identified using radioligands, establishing the receptor model as central to steroid signaling.^[16] The 1980s brought molecular insights via gene cloning, unveiling the nuclear receptor superfamily. The human glucocorticoid receptor cDNA was cloned in 1985 from MCF-7 breast cancer cells, revealing a DNA-binding domain homologous to oncogenes like v-erbA, suggesting a broader family of ligand-activated transcription factors.^[17] Subsequent clonings, including the estrogen receptor in 1986, confirmed structural conservation across steroid receptors, defining the superfamily that includes non-steroid members like thyroid hormone receptors.^[18] These advances enabled functional expression studies, solidifying the mechanism of steroid hormone action at the genetic level.^[19] The 1990s expanded the receptor landscape to non-classical forms, highlighting diverse signaling pathways. In 1997, a novel G protein-coupled receptor, GPR30 (later renamed GPER), was cloned from breast cancer cells, initially as an orphan receptor but soon linked to rapid estrogen responses independent of classical nuclear receptors. This discovery underscored membrane-associated steroid signaling, broadening the field beyond genomic actions. Structural biology advanced in the early 2000s, providing atomic-level insights into receptor-ligand interactions. The first X-ray crystal structure of a steroid receptor ligand-binding domain—the glucocorticoid receptor in complex with dexamethasone—was solved in 2002, revealing a helical fold that accommodates ligands and recruits coactivators, facilitating rational drug design for hormone-related disorders.^[20] This milestone, followed by structures of other steroid receptors like the estrogen receptor in 2004, transformed understanding of conformational dynamics and therapeutic targeting.^[21]

Classical Nuclear Receptors

Structure and domains

Classical steroid hormone receptors (SHRs), such as the estrogen receptor (ER), glucocorticoid receptor (GR), androgen receptor (AR), progesterone receptor (PR), and mineralocorticoid receptor (MR), are intracellular transcription factors belonging to the nuclear receptor superfamily. These proteins exhibit a modular architecture, typically comprising 500–900 amino acids, and exist as monomers in their unliganded state but form homodimers upon ligand binding to enhance DNA interaction and transcriptional activity.^[22]^[23] The conserved domain organization includes an N-terminal A/B domain, a central DNA-binding domain (DBD), a flexible hinge region, and a C-terminal ligand-binding domain (LBD), which collectively enable ligand recognition, DNA binding, and co-regulator recruitment.^[24] The N-terminal A/B domain, also known as the transactivation domain, is the most variable region among SHRs, ranging from 30–500 amino acids in length, and is often intrinsically disordered with a high propensity for random coil conformation. It harbors activation function 1 (AF1), which mediates ligand-independent transactivation by recruiting transcriptional co-activators and is regulated by post-translational modifications such as phosphorylation at specific serine residues, which can enhance or modulate receptor activity.^[23]^[25] For instance, in the GR, phosphorylation within AF1 influences its interaction with the basal transcriptional machinery. The A/B domain's flexibility allows it to adopt ordered conformations upon binding partners, contributing to context-specific gene regulation.^[23] The central DBD, or C domain, is highly conserved across SHRs, spanning approximately 65–70 amino acids, and features two zinc finger motifs formed by eight cysteine residues coordinating four zinc ions. The first zinc finger contains a proximal box (P-box) with residues like GR's Gly-Ser-Ala-Cys that recognize specific hormone response elements (HREs) in DNA, such as the inverted palindromic GRE consisting of two AGAACA half-sites separated by a three-nucleotide spacer (5'-AGAACAnnnTGTTCT-3'). The second zinc finger includes a dimerization box (D-box) that facilitates receptor dimerization on DNA. Early structures, including the 1990 NMR solution structure of the free GR DBD and the 1991 crystal structure of the rat GR DBD bound to DNA, revealed how these zinc fingers insert into the major groove of DNA for sequence-specific interactions.^[26]^[27]^[22] The hinge region, or D domain, is a flexible linker of 40–65 amino acids connecting the DBD and LBD, exhibiting the least sequence conservation among SHRs. It contains nuclear localization signals (NLS) essential for receptor translocation to the nucleus and serves as a site for post-translational modifications like sumoylation, which can fine-tune receptor function. This domain's plasticity allows conformational adjustments during dimerization and co-regulator binding.^[22]^[24] The C-terminal LBD, encompassing the E and F domains (approximately 250 amino acids), forms a globular structure with 11–12 α-helices arranged in an antiparallel sandwich, creating a hydrophobic pocket for high-affinity steroid ligand binding. Helix 12 within the LBD constitutes activation function 2 (AF2), which repositions upon ligand binding to form a co-activator binding groove, recruiting proteins with LXXLL motifs. Ligand specificity arises from pocket residues; for example, the AR's LBD prefers androgens like testosterone due to bulky residues like Met895 that exclude estrogens, as shown in crystal structures. In the unliganded state, the LBD associates with chaperone complexes, including HSP90, to maintain an open conformation and prevent premature activation. Seminal crystal structures from the late 1990s and early 2000s, such as PDB entry 1ERE for the ERα LBD bound to estradiol, illustrated these ligand-induced conformational shifts, while PDB 2AM9 for the AR LBD with testosterone highlighted androgen-specific features.^[28]^[22]^[29] The F domain, present in some SHRs like ER, extends the LBD and modulates ligand-dependent activity without directly binding the steroid.^[23]

Mechanism of genomic action

In the unliganded state, steroid hormone receptors are stabilized by binding to heat shock protein 90 (HSP90) chaperones, which maintain their inactivity and proper folding. For receptors such as the glucocorticoid receptor (GR), this chaperone-bound complex is predominantly localized in the cytoplasm, whereas for the estrogen receptor (ER), it is primarily nuclear.^[30]^[31] Ligand binding to the ligand-binding domain (LBD) triggers a conformational change that dissociates the HSP90 complex, exposing the nuclear localization signal (NLS) in the hinge region and enabling nuclear translocation for cytoplasmic receptors like GR. This process also promotes receptor dimerization, essential for subsequent DNA interactions. The binding exhibits high affinity, with dissociation constants (Kd) typically in the range of 1-10 nM, reflecting the physiological concentrations of steroid hormones.^[6]^[32] The simple equilibrium for this binding is:

\text{Receptor} + \text{Hormone} \rightleftharpoons \text{RH complex}

where the association constant is given by K_a = \frac{[\text{RH}]}{[\text{R}][\text{H}]}.^[32] The dimerized, ligand-bound receptors then bind to specific hormone response elements (HREs) in the DNA, such as the inverted palindromic sequence AGGTCA half-sites for ER. In the absence of ligand, corepressors like nuclear receptor corepressor (NCoR) associate with the receptor to inhibit transcription, but ligand binding shifts this to recruitment of coactivators, including steroid receptor coactivator-1 (SRC-1), which interacts via LXXLL motifs with the activation function-2 (AF2) surface in the LBD.^[6]^[33] This coactivator complex enhances chromatin accessibility at enhancers and promoters, facilitating the recruitment of RNA polymerase II and the basal transcription machinery to initiate target gene transcription. For instance, activated GR upregulates anti-inflammatory genes such as FKBP5, contributing to resolved inflammatory responses. The residence time of the activated receptor on DNA is relatively short (on the order of seconds to minutes), enabling dynamic cycling and regulated gene expression changes.^[34]^[35]

Non-Classical Receptors

Membrane-bound nuclear receptors

Membrane-bound nuclear receptors represent a subset of classical steroid hormone receptors, such as estrogen receptor alpha (ERα) and beta (ERβ) as well as the androgen receptor (AR), that localize to the plasma membrane to facilitate rapid, non-transcriptional signaling. These receptors maintain the core modular structure of their nuclear counterparts, including DNA-binding and ligand-binding domains, but a small fraction—approximately 5-10% of total cellular ERα and ERβ—is targeted to the membrane through post-translational modifications.^[36]^[37] Palmitoylation, mediated by DHHC-7 and DHHC-21 acyltransferases, attaches palmitic acid to cysteine residues in the ligand-binding domain (e.g., Cys447 in human ERα), anchoring the receptors to cholesterol-rich domains like caveolae and lipid rafts via interactions with caveolin-1.^[38]^[39]^[40] Myristoylation plays a lesser role but can contribute to membrane association in certain contexts for these receptors.^[41] Upon ligand binding, such as estradiol for ERα or testosterone for AR, these membrane-bound receptors do not translocate to the nucleus but instead rapidly associate with transmembrane proteins to initiate signaling cascades. For instance, membrane ERα interacts with insulin-like growth factor 1 receptor (IGF1R), promoting downstream activation of pathways like PI3K/Akt, while membrane AR can engage epidermal growth factor receptor (EGFR) to modulate cell proliferation signals.^[42]^[43] A prominent example is membrane ER (mER), which, in endothelial cells, binds estradiol to activate endothelial nitric oxide synthase (eNOS) via Src kinase and PI3K, leading to nitric oxide production and acute vasodilation.^[44]^[45] These membrane variants differ from classical nuclear receptors in their dynamics and discovery. They exhibit shorter half-lives (typically 1-4 hours upon ligand binding) and higher protein turnover rates compared to nuclear forms, enabling quick responses to fluctuating hormone levels.^[46]^[47] Membrane localization was first identified in the 1990s through subcellular fractionation techniques that separated plasma membrane components from cytosolic and nuclear fractions in steroid-responsive cells.^[48]^[49]

G protein-coupled receptors

G protein-coupled estrogen receptor (GPER), also known as GPR30, is a seven-transmembrane G protein-coupled receptor (GPCR) that mediates rapid non-genomic effects of estrogens.^[50] It was cloned in 1997 from breast cancer tissue as an orphan receptor and later identified as an estrogen-binding protein.^[50] GPER exhibits high-affinity binding to 17β-estradiol with a dissociation constant (Kd) of approximately 3 nM.^[51] Upon ligand binding, GPER couples to both Gαs and Gαi proteins, leading to bidirectional modulation of adenylyl cyclase activity and intracellular cAMP levels.^[52] Activation of GPER triggers multiple downstream signaling cascades, including phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) via the mitogen-activated protein kinase (MAPK) pathway and activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway, which promote cell survival and proliferation.^[53] Additionally, GPER stimulates phospholipase C (PLC) to generate inositol trisphosphate (IP3), resulting in intracellular calcium mobilization from endoplasmic reticulum stores.^[53] These rapid signaling events contribute to non-genomic estrogen actions, distinct from classical nuclear receptor pathways.^[53] GPER is ubiquitously expressed across tissues, with particularly high levels in the breast, ovary, and brain.^[54] In these tissues, GPER activation influences cellular processes such as proliferation and migration; for instance, in breast and ovarian cancer cells, estrogen stimulation of GPER enhances tumor cell motility and invasiveness through ERK1/2 and PI3K/Akt signaling.^[55] Beyond GPER, membrane progestin receptors (mPRs) represent another class of steroid-binding receptors with G protein-coupling properties, belonging to the progestin and AdipoQ receptor (PAQR) family.^[56] Unlike classical GPCRs, mPRs feature a distinct seven-transmembrane topology but associate with inhibitory G proteins (Gαi) to suppress adenylyl cyclase activity upon progestin binding.^[56] This signaling is well-documented in fish and rodent models, where mPRs mediate rapid progesterone effects on oocyte maturation and sperm chemotaxis, though their roles and expression in human physiology remain less clearly defined.^[56] Recent studies in the 2020s have highlighted the neuroprotective potential of GPER activation using selective agonists like G-1. For example, G-1 administration in animal models of Parkinson's disease reduces neuroinflammation and dopaminergic neuron loss by modulating microglial activation and ERK1/2 signaling.^[52] Similarly, G-1 confers protection against cerebral ischemia in ovariectomized rats by attenuating inflammatory responses and apoptosis via GPER-mediated pathways.^[57]

Ion channels and other effectors

Steroid hormones can directly modulate ion channels through non-receptor mechanisms, enabling rapid cellular responses independent of genomic transcription. For instance, estrogens enhance the activity of big potassium (BK) channels in various cell types, including vascular smooth muscle and neurons, by increasing channel open probability and burst duration without involving classical nuclear receptors.^[58] This activation occurs via nongenomic pathways, such as nitric oxide-mediated phosphorylation of the channel's β subunit, leading to membrane hyperpolarization and reduced excitability within seconds to minutes.^[59] Similarly, progesterone metabolites like allopregnanolone directly bind to and potentiate GABA_A receptors, which function as chloride channels, enhancing inhibitory chloride influx and promoting neuronal silencing.^[60] At low concentrations, allopregnanolone increases the frequency and duration of channel openings in response to GABA, while higher doses can directly gate the channel.^[61] Receptor-mediated modulation also plays a key role, where membrane-associated pools of steroid receptors influence voltage-gated calcium channels (VGCCs) to alter cellular excitability. Membrane androgen receptors (AR) and glucocorticoid receptors (GR) can rapidly regulate L-type VGCCs, such as CaV1.2, through protein-protein interactions or signaling cascades that adjust channel gating and calcium influx.^[62] For example, testosterone, acting via nonclassical AR signaling at the plasma membrane, opens ATP-sensitive potassium (KATP) channels in vascular smooth muscle cells, promoting potassium efflux, hyperpolarization, and vasodilation independent of endothelial factors.^[63] This effect is direct and occurs within minutes, as evidenced by increased single-channel activity in patch-clamp studies.^[64] Recent research highlights synergies between steroid hormones and vitamin D in regulating ion channels; for instance, sex steroids and vitamin D together modulate expression and function of channels like TRPV5 and L-type VGCCs in hormone-sensitive tissues, influencing calcium homeostasis through both transcriptional and rapid nongenomic actions.^[65] These modulations often involve post-translational mechanisms, such as phosphorylation of ion channels by kinases activated downstream of steroid receptor signaling, without requiring DNA binding. GPER-mediated estrogen signaling, for example, activates protein kinase A (PKA), which phosphorylates targets including potassium and calcium channels, thereby fine-tuning their conductance and voltage sensitivity.^[66] Such rapid effects are exemplified by estradiol's potentiation of L-type VGCCs in hippocampal neurons, increasing calcium influx to support synaptic plasticity within seconds.^[67] Overall, these interactions enable steroids to elicit fast, localized changes in membrane potential and ion flux, distinct from slower genomic pathways.

SHBG receptor complex

Sex hormone-binding globulin (SHBG) is a homodimeric glycoprotein, approximately 90–100 kDa in size, primarily synthesized and secreted by hepatocytes in the liver. It exhibits high-affinity binding to androgens such as testosterone and dihydrotestosterone (DHT), as well as estrogens like estradiol, with dissociation constants (Kd) around 1 nM, thereby serving as the principal carrier for these steroids in plasma. In humans, SHBG binds 40–65% of circulating testosterone and 20–40% of estradiol, significantly influencing their bioavailability by limiting free hormone diffusion while potentially facilitating targeted delivery to tissues.^[68]^[69]^[70] The SHBG receptor (SHBG-R) is hypothesized to be a multiprotein complex on the cell membrane that binds SHBG to facilitate non-classical steroid signaling and potentially cellular uptake, though its exact molecular identity and mechanisms remain under investigation. Binding sites were first detected in the late 1980s with Kd ~10 nM on plasma membranes of target cells like those in the prostate and breast, and activity was further characterized in the 1990s as facilitating rapid steroid actions independent of intracellular nuclear receptors. In certain tissues, such as leiomyomas, SHBG-R co-localizes with caveolin-1 in caveolae structures, suggesting involvement in membrane microdomain organization. Proposed mechanisms include promotion of endocytosis of SHBG-bound steroids, primarily via the endocytic receptor megalin (a low-density lipoprotein receptor family member) in steroid-responsive tissues like the reproductive tract, allowing internalized steroids to dissociate and access intracellular receptors; however, this process remains controversial. This mechanism challenges the traditional free hormone hypothesis by demonstrating active transport rather than passive diffusion alone.^[71]^[72]^[73]^[74] Upon binding an appropriate steroid, the SHBG-steroid-SHBG-R complex has been reported to trigger G protein-mediated signal transduction, rapidly activating adenylyl cyclase to elevate intracellular cyclic AMP (cAMP) levels within minutes, though these signaling pathways are still debated. This non-genomic pathway modulates downstream effectors, including protein kinase A, influencing cellular processes like gene transcription indirectly. For instance, the DHT-SHBG complex enhances sperm motility in human semen samples, correlating with higher local SHBG isoform abundance and supporting fertility through rapid signaling in reproductive cells. Unlike classical nuclear receptors that directly bind free steroids for genomic effects, the SHBG-R complex primarily modulates steroid access to intracellular receptors while initiating these membrane-based signals.^[75]^[76]^[77] SHBG levels and function are tightly regulated, with plasma concentrations decreasing in conditions like obesity due to hyperinsulinemia and hepatic lipogenesis, which suppress hepatic synthesis and reduce overall hormone bioavailability. Genetic variants in the SHBG gene, such as single nucleotide polymorphisms in the promoter region (e.g., rs6259), are associated with altered SHBG expression and circulating levels, impacting sex steroid availability and contributing to metabolic and reproductive phenotypes. These regulatory aspects underscore SHBG's role as a modulator rather than a direct receptor, fine-tuning steroid hormone action across physiological contexts.^[78]^[79]

Signaling Integration

Non-genomic actions

Non-genomic actions of steroid hormone receptors refer to rapid signaling events that occur within seconds to minutes, mediated primarily through membrane-associated receptors or effectors, and independent of nuclear gene transcription. These effects contrast with the slower genomic pathways by enabling immediate physiological responses, such as alterations in ion fluxes, second messenger systems, and kinase activation, often without requiring de novo protein synthesis.^[80]^[81] Key signaling pathways activated by non-genomic steroid actions include the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) cascade, phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway, and protein kinase C (PKC) signaling. For instance, estrogen binding to the G protein-coupled estrogen receptor (GPER) rapidly phosphorylates endothelial nitric oxide synthase (eNOS) via Akt and ERK, leading to increased nitric oxide (NO) production and subsequent vasodilation in vascular endothelium. Similarly, these pathways facilitate quick modulation of intracellular calcium levels and cyclic AMP, contributing to diverse cellular responses across tissues.^[82]^[83] Representative examples illustrate the breadth of these actions. Progesterone, acting through membrane progestin receptors (mPRs), induces rapid oocyte maturation in species like Xenopus laevis by elevating intracellular calcium and activating phospholipase A2, promoting meiotic resumption without transcriptional involvement. Glucocorticoids exert fast anti-inflammatory effects via membrane glucocorticoid receptors (mGR), rapidly inhibiting pro-inflammatory cytokine release and modulating NFκB activity in immune cells, which supports immediate suppression of inflammation in conditions like asthma.^[84]^[85] These non-genomic actions provide advantages for fine-tuned, localized physiological regulation, such as enhancing neuronal excitability in response to steroids or enabling rapid behavioral adaptations in reproductive contexts. Evidence for their transcription-independent nature comes from experiments showing that inhibitors like actinomycin D, which block RNA synthesis, do not abolish these rapid effects, confirming reliance on pre-existing cellular machinery.^[80]^[84]^[81] Recent research as of 2024 has highlighted roles of adrenal gland macrophages in regulating glucocorticoid production through non-genomic interactions during stress, contributing to dynamic hormone modulation.^[86]

Cross-talk with other pathways

Steroid hormone receptors (SRs) engage in extensive cross-talk with other cellular signaling pathways, enabling integrated responses to diverse stimuli and fine-tuning physiological outcomes. This interplay occurs through both genomic and non-genomic mechanisms, where SRs modulate or are modulated by pathways such as those involving receptor tyrosine kinases, transcription factors, and metabolic regulators. Such interactions are crucial for processes like inflammation control, cell proliferation, and metabolic homeostasis, often involving shared co-regulators or indirect DNA binding modes.^[87]^[88] A prominent example of SR-pathway cross-talk is the ligand-independent transactivation of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) by estrogen receptor (ER). In breast cancer cells, ER can phosphorylate and activate EGFR/HER2 without estrogen binding, leading to downstream MAPK/ERK signaling that promotes cell survival and proliferation. This non-canonical activation occurs via matrix metalloproteinase-dependent release of EGFR ligands like heparin-binding EGF-like growth factor.^[89]^[90] Similarly, the glucocorticoid receptor (GR) exerts anti-inflammatory effects by inhibiting nuclear factor kappa B (NFκB) and c-Jun (a component of AP-1), preventing their transcriptional activity on pro-inflammatory genes such as interleukin-6 and tumor necrosis factor-alpha. GR achieves this through direct protein-protein interactions that sequester NFκB or compete for co-activators, thereby suppressing cytokine production in immune cells.^[91]^[92] Non-genomic cross-talk further amplifies SR signaling integration. The G protein-coupled estrogen receptor (GPER) links to MAPK pathways by transactivating growth factor receptors, including EGFR, via rapid calcium mobilization and Src kinase activation, which supports estrogen-dependent endothelial cell migration and vascular function.^[93] At the genomic level, SRs integrate with other pathways through shared co-regulators and feedback mechanisms. For instance, ER and AP-1 (comprising c-Fos/c-Jun) co-occupy promoters via the histone acetyltransferases p300/CBP, which bridge their activities to regulate genes involved in cell growth; this tethering allows ER to enhance AP-1-driven transcription in a ligand-dependent manner. GR autoregulation exemplifies feedback loops, where ligand-bound GR downregulates its own expression by binding negative glucocorticoid response elements, limiting excessive glucocorticoid signaling and maintaining homeostasis in stress responses.^[94]^[95] In cancer contexts, ER cross-talk with the PI3K/AKT/mTOR pathway drives resistance to tamoxifen by sustaining cell survival signals; PI3K activation phosphorylates ER at serine 167, enhancing its transcriptional activity independently of estrogen, thus bypassing endocrine blockade. Mechanistically, these integrations operate via distinct DNA binding models: direct binding to composite elements, where SRs and partner factors (e.g., NFκB) simultaneously contact adjacent response elements for synergistic activation, or tethering, where SRs indirectly associate with DNA through protein-protein interactions with DNA-bound partners like AP-1, facilitating transrepression without canonical SR DNA motifs. Tethering predominates in anti-inflammatory contexts, such as GR-NFκB inhibition, while composite elements support cooperative gene induction.^[96]^[97]

Clinical Relevance

Role in diseases

Dysregulation of steroid hormone receptors plays a central role in numerous pathologies, often through mutations, overexpression, or altered signaling that disrupts normal hormonal control of cellular processes. In cancers, aberrant receptor activity promotes uncontrolled proliferation and therapeutic resistance. For instance, overexpression of the estrogen receptor (ER) alpha occurs in approximately 70-80% of breast cancers, driving tumor growth via enhanced estrogen-dependent transcription.^[98] Similarly, mutations in the androgen receptor (AR) are implicated in castration-resistant prostate cancer, where they enable ligand-independent activation and confer resistance to antiandrogen therapies like enzalutamide.^[99] In hematological malignancies, the glucocorticoid receptor (GR) is essential for inducing apoptosis in leukemic cells, but polymorphisms or downregulation lead to glucocorticoid resistance in up to 20-30% of acute lymphoblastic leukemia cases, worsening prognosis.^[100] Endocrine disorders frequently arise from steroid receptor defects that impair hormone responsiveness. Complete androgen insensitivity syndrome, a form of 46,XY disorder of sex development, results from over 1,000 identified mutations in the AR gene, leading to resistance to androgens and female external genitalia despite male gonadal development.^[101] In polycystic ovary syndrome (PCOS), altered progesterone receptor (PR) expression in the endometrium contributes to progesterone resistance, disrupting normal menstrual cycling and increasing risks of endometrial hyperplasia; studies show reduced PR levels and impaired downstream signaling in PCOS patients compared to controls.^[102] Metabolic and inflammatory conditions are also linked to steroid receptor variants. GR polymorphisms, such as the A3669G variant, are associated with relative glucocorticoid resistance that attenuates metabolic complications like diabetes and altered lipid profiles in patients with Cushing's syndrome.^[103] Recent research highlights the role of nuclear receptors (NRs) in non-alcoholic fatty liver disease (NAFLD) through immunometabolic pathways; for example, NRs like PPARs and FXR regulate lipid homeostasis and inflammation, and their dysregulation exacerbates steatosis and fibrosis, with 2025 studies emphasizing FXR agonists for modulating immune responses in metabolic dysfunction-associated steatotic liver disease.^[104] Neurological diseases involve steroid receptors in neuroprotection and rapid signaling. Loss of ER and G protein-coupled estrogen receptor (GPER) function contributes to Alzheimer's disease progression, where GPER activation normally mitigates amyloid-β toxicity and tau pathology, but its downregulation in aging brains heightens vulnerability to neurodegeneration.^[105] In stroke, rapid non-genomic actions of steroid receptors, such as progesterone receptor-mediated signaling, provide neuroprotection by reducing ischemic injury through anti-inflammatory and anti-apoptotic effects, as demonstrated in preclinical models of cerebral ischemia.^[106] Clinically, these receptor dysregulations have significant implications; for example, about 70% of ER-positive breast cancers initially respond to endocrine therapies due to receptor dependency, though resistance develops in many cases via pathway crosstalk.^[107]

Therapeutic applications

Steroid hormone receptors are key targets for therapeutic interventions in hormone-dependent diseases, primarily through the use of selective agonists, antagonists, and modulators that exploit their ligand-binding properties to alter gene expression and cellular responses.^[108] Selective estrogen receptor modulators (SERMs) such as tamoxifen act as antagonists in breast tissue to inhibit estrogen-driven proliferation in estrogen receptor-positive (ER+) breast cancer, serving as a first-line endocrine therapy that reduces recurrence risk by approximately 50% in early-stage disease.^[109] Similarly, androgen receptor (AR) antagonists like enzalutamide bind to the AR ligand-binding domain, preventing nuclear translocation and DNA binding, thereby suppressing tumor growth in metastatic castration-resistant prostate cancer (mCRPC) and extending overall survival by 4-5 months in post-chemotherapy patients.^[110] Glucocorticoid receptor (GR) agonists, exemplified by dexamethasone, mimic endogenous cortisol to induce anti-inflammatory effects by promoting transrepression of pro-inflammatory genes, widely used in conditions like rheumatoid arthritis and acute lymphoblastic leukemia to rapidly suppress cytokine storms.^[111] Emerging therapies target non-classical steroid hormone receptors to harness rapid, non-genomic signaling for cardioprotective and metabolic benefits. G protein-coupled estrogen receptor (GPER) agonists, such as G1, activate GPER to elicit vasodilatory and anti-fibrotic effects in preclinical models of cardiac ischemia/reperfusion injury, with ongoing research exploring their potential in cardiovascular protection through endothelial nitric oxide synthase activation.^[112] These agents show promise in clinical development for metabolic homeostasis, where GPER modulation improves insulin sensitivity and reduces adiposity in animal models of obesity and diabetes.^[113] Advanced strategies focus on coregulator modulation to overcome limitations of traditional ligands, including proteolysis-targeting chimeras (PROTACs) that induce ubiquitin-mediated degradation of receptors. AR-targeted PROTACs like ARV-110 and ARV-766 are in phase 1/2 clinical trials for mCRPC, demonstrating partial responses in 20-30% of heavily pretreated patients by selectively depleting AR protein levels without affecting wild-type steroid receptors.^[114] Similarly, ER degrader PROTACs such as ARV-471 (vepdegestrant) have advanced to phase 3 trials for ER+ breast cancer, with the VERITAC-2 study (completed in 2025) demonstrating a statistically significant improvement in progression-free survival (median 2.9 months longer than fulvestrant) in patients with ESR1 mutations and prior endocrine therapy. Early phase 1 data showed clinical benefit rates up to 40% in pretreated patients.^[115]^[116] Recent advances in 2025 emphasize nuclear receptor (NR)-targeted therapies for metabolic diseases, including selective GR agonists (SEGRAs) designed to preferentially induce transrepression for anti-inflammatory effects while minimizing transactivation-linked metabolic side effects like hyperglycemia.^[117] These SEGRAs, such as those in preclinical optimization, aim to treat conditions like metabolic syndrome by dissociating therapeutic efficacy from adverse glucose dysregulation observed in classical glucocorticoids.^[118] Therapeutic challenges include resistance mechanisms driven by receptor mutations and pathway cross-talk, complicating long-term efficacy. For instance, ESR1 mutations occur in approximately 30% of ER+ breast cancers resistant to endocrine therapy, leading to constitutive ER activation and relapse rates of up to 30% despite initial SERM responsiveness.^[119] In prostate cancer, AR splice variants confer enzalutamide resistance in 20-40% of cases, underscoring the need for combination strategies targeting multiple signaling nodes.^[120]

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Nov 1, 2023 · This document is the International Union of Basic and Clinical Pharmacology CXIII update on the Nuclear Receptor Superfamily from 2023.
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It is wholly 90 years since the first report of the isolation and characterisation of progesterone by Willard M. Allen and George W. Corner.
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In the 1920s and 1930s, Adolf Butenandt, Tadeus Reichstein and Edward Adelbert Doisy discovered and characterized various steroid hormones, including oestrogen ...
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Elwood V. Jensen (1920–2012): Father of the nuclear receptors - NIH
Mar 4, 2013 · Jensen is popularly credited with the discovery of the mammalian estrogen receptor, and the promulgation of this important molecule as a key player in female ...
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Review Fifty years ago: The quest for steroid hormone receptors
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Elwood V. Jensen (1920–2012): Father of the nuclear receptors
Mar 4, 2013 · ... cloning of the estrogen receptor in the Chambon laboratory in 1986. The work of Evans on the nuclear receptor superfamily awakened ...
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Nuclear Receptor Superfamily: A Rosetta Stone for Physiology
In the December 1985 issue of Nature, we described the cloning of the first nuclear receptor cDNA encoding the human glucocorticoid receptor (GR) (1). In the 20 ...
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Crystal Structure of the Glucocorticoid Receptor Ligand Binding ...
Crystal structure of the glucocorticoid receptor ligand binding domain reveals a novel mode of receptor dimerization and coactivator recognition.
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Structure-Based Design of Estrogen Receptor-β Selective Ligands
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The role of FKBP5, a co-chaperone of the glucocorticoid receptor in ...
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The role of membrane ERα signaling in bone and other major ...
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Mutation of the palmitoylation site of estrogen receptor α in vivo ...
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Rapid Actions of the Nuclear Progesterone Receptor through cSrc in ...
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Down-regulation of IGF-1R clearly blocked ERα membrane translocation in the cells (Fig. 4 Ah and Bc), confirming the role of IGF-1R on ERα membrane association.
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Membrane Estrogen Receptor Engagement Activates Endothelial ...
Here we demonstrate for the first time, to our knowledge, that E2 rapidly induces phosphorylation and activation of eNOS through the phosphatidylinositol 3 (PI3)- ...Missing: mER | Show results with:mER
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Membrane estrogen receptor engagement activates endothelial ...
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Upon initial hormone treatment, ERα half-life is shortened from 3 to 1 h. However, ERα half-life increases over time, achieving a half-life of ∼6 h in 72 h of ...<|control11|><|separator|>
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Membrane and Nuclear Estrogen Receptor Alpha Actions
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Steroid hormones: Interactions with membrane-bound receptors
them were cloned in the 1980s and 1990s. These discoveries were the origins of the classical model for steroid hormone action (Figure 1a). In this model ...
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G Protein-Coupled Estrogen Receptor: A Potential Therapeutic ...
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GPER1 - G-protein coupled estrogen receptor 1 | UniProtKB - UniProt
Binds 17-beta-estradiol (E2) in plasma membranes with high affinity (Kd is 3.3 nM) and displays rapid kinetics of association and dissociation. 3 ...
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G Protein–Coupled Estrogen Receptor GPER - PubMed Central - NIH
Competitive binding assays with radiolabeled or fluorescent probes revealed that E2 has the highest GPER binding affinity (3–6 nM) and greater than 1,000-fold ...Gper Ligands And... · Gper Pharmacology With... · Xenoestrogens As Gper...
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Role of G Protein-Coupled Estrogen Receptor in Digestive System ...
Apr 14, 2021 · ... MAPK/ERK and PI3K/AKT pathways. Additionally, the additional signals activated by GPER include PLC/IP3/calcium mobilization, PKC, and Hippo ...
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NHERF1, a novel GPER associated protein, increases stability and ...
Aug 23, 2016 · GPER is extensively expressed in numerous tissues such as breast, uterus, ovary and brain. It has been reported to play physiological roles ...
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Role of G Protein-Coupled Estrogen Receptor in Cancer Progression
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The modulation of potassium channels by estrogens facilitates ...
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Estrogenic Modulation of Ionic Channels, Pumps and Exchangers in ...
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In close proximity to 5-HT releasing sites, activated GR rapidly triggers L-type VGCC-dependent vesicular 5-HT release.Missing: pools excitability
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Taken together, these four studies provide evidence that testosterone-induced vasodilatation occurs via potassium channel opening, having a modulatory effect ...
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Sex Hormone-Binding Globulin and Metabolic Syndrome in ... - MDPI
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Recent Advances on Sex Hormone-Binding Globulin Regulation by ...
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Sex hormone-binding globulin is synthesized in target cells
**Summary of SHBG Receptor Discovery and Related Pathways:**
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Expression of sex hormone-binding globulin, oxytocin receptor ...
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Human Sperm Sex Hormone-Binding Globulin Isoform
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Human sex hormone–binding globulin variants associated with ... - JCI
The genetic screening methods reported here will help identify individuals in whom genetic variants contribute to low serum SHBG levels, as opposed to others ...
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The Role of G Protein-Coupled Estrogen Receptor (GPER) in ... - NIH
GPER phosphorylates eNOS through the non-genomic Akt/ERK pathway, which in turn promotes NO production. NO produced in ECs stimulates sGC in VSMCs to produce ...
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Non-genomic Effects of Estrogen on Cell Homeostasis ... - Frontiers
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Making sense of cross-talk between steroid hormone receptors and ...
This review provides an overview of the primary ways in which steroid hormone receptor and growth factor cross-talk occurs, using the human progesterone ...
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Genome-wide crosstalk between steroid receptors in breast and ...
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Epidermal growth factor receptor (EGFR) transactivation by estrogen ...
... estrogen receptor (ER)-negative human breast cancer cells [Molecular Endocrinology 14 (2000) 1649]. This finding is consistent with a growing body of ...
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Epidermal growth factor receptor (EGFR) transactivation by estrogen ...
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The glucocorticoid receptor and NFĸB in good times and bad
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Nuclear Factor-κ B Repression in Antiinflammation and ...
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Cross-talk between GPER and growth factor signaling - ScienceDirect
In particular, the cross-talk between GPCRs and growth factor receptors has recently emerged as a signaling mechanism involved in cancer growth, angiogenesis ...
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Antagonizing effects of membrane-acting androgens on the ... - Nature
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Nuclear Integration of Glucocorticoid Receptor and Nuclear Factor ...
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Overview of the relevance of PI3K pathway in HR-positive breast ...
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Glucocorticoid activation of anti-inflammatory macrophages protects ...
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Article DNA Binding of the Glucocorticoid Receptor Is Not Essential ...
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Glucocorticoid Receptor Transcriptional Activity Determined by ...
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Estrogen-receptor positive breast cancer: Diagnosis, response to ...
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The future of androgen receptor targeting in prostate cancer
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Glucocorticoid Resistance in Acute Lymphoblastic Leukemia: BIM ...
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Different types of androgen receptor mutations in patients with ...
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Endometrial progesterone resistance and PCOS
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Orphan Nuclear Receptors in Metabolic Dysfunction-associated ...
Jun 19, 2025 · This review specifically focuses on elucidating the critical contributions of various ONRs to the pathogenesis of metabolic dysfunction- ...
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G-protein coupled estrogen receptor 1, amyloid-β, and tau tangles in ...
May 15, 2024 · Accumulation of amyloid-β (Aβ) and tau tangles are hallmarks of Alzheimer's disease (AD). It is hypothesized that Aβ accelerates tau ...
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Review Neurosteroids and their receptors in ischemic stroke
Neurosteroids receptors play important roles in neuroprotection mediated by these hormones. Membrane and intracellular receptors are both involved in the ...
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The Effect of Selective Estrogen Receptor Modulators (SERMs ... - NIH
Tamoxifen, the prototypical SERM, is extensively used for targeted therapy of ER positive breast cancers. For almost three decades, this drug has been as a ...
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Tamoxifen - StatPearls - NCBI Bookshelf - NIH
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Enzalutamide: A New Agent for the Prostate Cancer Treatment ... - NIH
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The Role of Glucocorticoids in Inflammatory Diseases - PMC
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GPER mediates estrogen cardioprotection against epinephrine ...
May 20, 2021 · In this study, we investigated the effects and mechanism of GPER on epinephrine (Epi)-induced cardiac stress. SCM was developed with a high dose ...Missing: clinical trials
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GPER in metabolic homeostasis and disease - PubMed
Aug 26, 2025 · Rapid advancements in GPER agonist and antagonist research have highlighted the therapeutic potential of GPER agonists for treating metabolic ...
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Study Details | NCT03888612 | Trial of ARV-110 in Patients With ...
Phase 1/2 dose escalation study to assess the safety and tolerability of ARV-110 in men with mCRPC who have progressed on prior approved systemic therapies ...
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Study Details | NCT05654623 | ClinicalTrials.gov - ClinicalTrials.gov
The purpose of this study is to learn about the safety and effects of the study medicine ARV-471 (PF-07850327, vepdegestrant) compared to fulvestrant (FUL)
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Fresh insights into glucocorticoid-induced diabetes mellitus and new ...
May 18, 2022 · Long-term use of glucocorticoids is severely hampered by undesirable metabolic complications, including the development of type 2 diabetes mellitus.
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Selective steroid receptor modulators, degraders and PROTACs
This review highlights recent advancements in SNuRMs and SNuRDs for managing NRs-associated endocrine/metabolic disorders.
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Estrogen-Receptor Loss and ESR1 Mutation in Estrogen ... - PubMed
Aug 30, 2024 · We conclude that ER loss and ESR1 mutation together account for 30% of the resistance to endocrine therapy. Keywords: ESR1 mutation; breast ...Missing: relapse | Show results with:relapse
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Current uses and resistance mechanisms of enzalutamide ... - PubMed
Sep 20, 2024 · Enzalutamide is an effective prostate cancer therapy that is currently used in biochemically-recurrent and metastatic disease, and for both castration ...