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Estrogen receptor

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Estrogen receptors (ERs) are proteins found in cells that function as receptors for the hormone estrogen (17β-estradiol).[1] There are two main classes of ERs. The first includes the intracellular estrogen receptors, namely ERα and ERβ, which belong to the nuclear receptor family. The second class consists of membrane estrogen receptors (mERs), such as GPER (GPR30), ER-X, and Gq-mER, which are primarily G protein-coupled receptors. This article focuses on the nuclear estrogen receptors (ERα and ERβ).

estrogen receptor 1 (ER-alpha)
A dimer of the ligand-binding region of ERα (PDB rendering based on 3erd​).
Identifiers
SymbolESR1
Alt. symbolsER-α, NR3A1
NCBI gene2099
HGNC3467
OMIM133430
PDB1ERE
RefSeqNM_000125
UniProtP03372
Other data
LocusChr. 6 q24-q27
Search for
StructuresSwiss-model
DomainsInterPro
estrogen receptor 2 (ER-beta)
A dimer of the ligand-binding region of ERβ (PDB rendering based on 1u3s​).
Identifiers
SymbolESR2
Alt. symbolsER-β, NR3A2
NCBI gene2100
HGNC3468
OMIM601663
PDB1QKM
RefSeqNM_001040275
UniProtQ92731
Other data
LocusChr. 14 q21-q22
Search for
StructuresSwiss-model
DomainsInterPro

Upon activation by estrogen, intracellular ERs undergo translocation to the nucleus where they bind to specific DNA sequences. As DNA-binding transcription factors, they regulate the activity of various genes. However, ERs also exhibit functions that are independent of their DNA-binding capacity.[2] These non-genomic actions contribute to the diverse effects of estrogen signaling in cells.

Estrogen receptors (ERs) belong to the family of steroid hormone receptors, which are hormone receptors for sex steroids. Along with androgen receptors (ARs) and progesterone receptors (PRs), ERs play crucial roles in regulating sexual maturation and gestation. These receptors mediate the effects of their respective hormones, contributing to the development and maintenance of reproductive functions and secondary sexual characteristics.

Genes

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In humans, the two forms of the estrogen receptor are encoded by different genes, ESR1 and ESR2 on the sixth and fourteenth chromosome (6q25.1 and 14q23.2), respectively.

Structure

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The domain structures of ERα and ERβ, including some of the known phosphorylation sites involved in ligand-independent regulation.
Estrogen receptor alpha
N-terminal AF1 domain
Identifiers
SymbolOest_recep
PfamPF02159
InterProIPR001292
SCOP21hcp / SCOPe / SUPFAM
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
Estrogen and estrogen related receptor C-terminal domain
Identifiers
SymbolESR1_C
PfamPF12743
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

There are two different forms of the estrogen receptor, usually referred to as α and β, each encoded by a separate gene (ESR1 and ESR2, respectively). Hormone-activated estrogen receptors form dimers, and, since the two forms are coexpressed in many cell types, the receptors may form ERα (αα) or ERβ (ββ) homodimers or ERαβ (αβ) heterodimers.[3] Estrogen receptor alpha and beta show significant overall sequence homology, and both are composed of five domains designated A/B through F (listed from the N- to C-terminus; amino acid sequence numbers refer to human ER).[citation needed]

The N-terminal A/B domain is able to transactivate gene transcription in the absence of bound ligand (e.g., the estrogen hormone). While this region is able to activate gene transcription without ligand, this activation is weak and more selective compared to the activation provided by the E domain. The C domain, also known as the DNA-binding domain, binds to estrogen response elements in DNA. The D domain is a hinge region that connects the C and E domains. The E domain contains the ligand binding cavity as well as binding sites for coactivator and corepressor proteins. The E-domain in the presence of bound ligand is able to activate gene transcription. The C-terminal F domain function is not entirely clear and is variable in length.[citation needed]

Due to alternative RNA splicing, several ER isoforms are known to exist. At least three ERα and five ERβ isoforms have been identified. The ERβ isoforms receptor subtypes can transactivate transcription only when a heterodimer with the functional ERß1 receptor of 59 kDa is formed. The ERß3 receptor was detected at high levels in the testis. The two other ERα isoforms are 36 and 46kDa.[4][5]

Only in fish, but not in humans, an ERγ receptor has been described.[6]

Tissue distribution

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Both ERs are widely expressed in different tissue types, however there are some notable differences in their expression patterns:[7]

The ERs are regarded to be cytoplasmic receptors in their unliganded state, but visualization research has shown that only a small fraction of the ERs reside in the cytoplasm, with most ER constitutively in the nucleus.[11] The "ERα" primary transcript gives rise to several alternatively spliced variants of unknown function.[12]

Signal transduction

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Since estrogen is a steroidal hormone, it can readily diffuse through the phospholipid membranes of cells due to its lipophilic nature. As a result, estrogen receptors can be located intracellularly and do not necessarily need to be membrane-bound to interact with estrogen.[13] However, both intracellular and membrane-bound estrogen receptors exist, each mediating different cellular responses to estrogen.[14]

Genomic

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In the absence of hormone, estrogen receptors are predominantly located in the cytoplasm.[15] Hormone binding triggers a series of events, beginning with the migration of the receptor from the cytoplasm to the nucleus. This is followed by the dimerization of the receptor, where two receptor molecules join together. Finally, the receptor dimer binds to specific DNA sequences known as hormone response elements, initiating the process of gene regulation.

The DNA/receptor complex then recruits other proteins responsible for transcription of downstream DNA into mRNA and ultimately protein, resulting in changes in cell function.[15] Estrogen receptors are also present within the cell nucleus, and both estrogen receptor subtypes (ERα and ERβ) contain a DNA-binding domain, allowing them to function as transcription factors regulating protein production.[16]

The receptor also interacts with transcription factors such as activator protein 1 and Sp-1 to promote transcription, via several coactivators including PELP-1.[15] Tumor suppressor kinase LKB1 coactivates ERα in the cell nucleus through direct binding, recruiting it to the promoter of ERα-responsive genes. LKB1's catalytic activity enhances ERα transactivation compared to catalytically deficient LKB1 mutants.[17] Direct acetylation of estrogen receptor alpha at lysine residues in the hinge region by p300 regulates transactivation and hormone sensitivity.[18]

Non-genomic

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Nuclear estrogen receptors can also associate with the cell surface membrane and undergo rapid activation upon cellular exposure to estrogen.[19][20]

Some ERs interact with cell membranes by binding to caveolin-1 and forming complexes with G proteins, striatin, receptor tyrosine kinases (e.g., EGFR and IGF-1), and non-receptor tyrosine kinases (e.g., Src).[2][19] Membrane-bound ERs associated with striatin can increase levels of Ca2+ and nitric oxide (NO).[21] Interactions with receptor tyrosine kinases trigger signaling to the nucleus via the mitogen-activated protein kinase (MAPK/ERK) and phosphoinositide 3-kinase (Pl3K/AKT) pathways.[22]

Glycogen synthase kinase-3 (GSK)-3β inhibits nuclear ER transcription by preventing phosphorylation of serine 118 on nuclear ERα. The PI3K/AKT and MAPK/ERK pathways can phosphorylate GSK-3β, thereby removing its inhibitory effect, with the latter pathway acting via rsk.

17β-Estradiol has been shown to activate the G protein-coupled receptor GPR30.[23] However, the subcellular localization and precise role of this receptor remain controversial.[24]

Clinical significance

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Nolvadex (tamoxifen) 20 mg
 
Arimidex (anastrozole) 1 mg

Cancer

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Estrogen receptors are over-expressed in around 70% of breast cancer cases, referred to as "ER-positive", and can be demonstrated in such tissues using immunohistochemistry. Two hypotheses have been proposed to explain why this causes tumorigenesis, and the available evidence suggests that both mechanisms contribute:

The result of both processes is disruption of cell cycle, apoptosis and DNA repair, which increases the chance of tumour formation. ERα is certainly associated with more differentiated tumours, while evidence that ERβ is involved is controversial. Different versions of the ESR1 gene have been identified (with single-nucleotide polymorphisms) and are associated with different risks of developing breast cancer.[25]

Estrogen and the ERs have also been implicated in breast cancer, ovarian cancer, colon cancer, prostate cancer, and endometrial cancer. Advanced colon cancer is associated with a loss of ERβ, the predominant ER in colon tissue, and colon cancer is treated with ERβ-specific agonists.[26]

Endocrine therapy for breast cancer involves selective estrogen receptor modulators (SERMS), such as tamoxifen, which behave as ER antagonists in breast tissue, or aromatase inhibitors, such as anastrozole. ER status is used to determine sensitivity of breast cancer lesions to tamoxifen and aromatase inhibitors.[27] Another SERM, raloxifene, has been used as a preventive chemotherapy for women judged to have a high risk of developing breast cancer.[28] Another chemotherapeutic anti-estrogen, ICI 182,780 (Faslodex), which acts as a complete antagonist, also promotes degradation of the estrogen receptor.

However, de novo resistance to endocrine therapy undermines the efficacy of using competitive inhibitors like tamoxifen. Hormone deprivation through the use of aromatase inhibitors is also rendered futile.[29] Massively parallel genome sequencing has revealed the common presence of point mutations on ESR1 that are drivers for resistance, and promote the agonist conformation of ERα without the bound ligand. Such constitutive, estrogen-independent activity is driven by specific mutations, such as the D538G or Y537S/C/N mutations, in the ligand binding domain of ESR1 and promote cell proliferation and tumor progression without hormone stimulation.[30]

Menopause

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The metabolic effects of estrogen in postmenopausal women has been linked to the genetic polymorphism of estrogen receptor beta (ER-β).[31]

Aging

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Studies in female mice have shown that estrogen receptor-alpha declines in the pre-optic hypothalamus as they grow old. Female mice that were given a calorically restricted diet during the majority of their lives maintained higher levels of ERα in the pre-optic hypothalamus than their non-calorically restricted counterparts.[8]

Obesity

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A dramatic demonstration of the importance of estrogens in the regulation of fat deposition comes from transgenic mice that were genetically engineered to lack a functional aromatase gene. These mice have very low levels of estrogen and are obese.[32] Obesity was also observed in estrogen deficient female mice lacking the follicle-stimulating hormone receptor.[33] The effect of low estrogen on increased obesity has been linked to estrogen receptor alpha.[34]

SERMs for other treatment purposes

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SERMs are also being studied for the treatment of uterine fibroids[35] and endometriosis.[36] The evidence supporting the use of SERMs for treating uterine fibroids (reduction in size of fibroids and improving other clinical outcomes) is inconclusive and more research is needed.[35] It is also not clear if SERMs is effective for treating endometriosis.[36]

Estrogen insensitivity syndrome

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Estrogen insensitivity syndrome is a rare intersex condition with 5 reported cases, in which estrogen receptors do not function. The phenotype results in extensive masculinization. Unlike androgen insensitivity syndrome, EIS does not result in phenotype sex reversal. It is incredibly rare and is anologious to the AIS, and forms of adrenal hyperplasia. The reason why AIS is common and EIS is exceptionally rare is that XX AIS does not result in infertility, and therefore can be maternally inheirented, while EIS always results in infertility regardless of karyotype. A negative feedback loop between the endocrine system also occurs in EIS, in which the gonads produce markedly higher levels of estrogen for individuals with EIS (119–272 pg/mL XY and 750–3,500 pg/mL XX, see average levels) however no feminizing effects occur.[37][38]

Ligands

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Agonists

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Mixed (agonist and antagonist mode of action)

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Antagonists

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Affinities

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Affinities of estrogen receptor ligands for the ERα and ERβ
Ligand Other names Relative binding affinities (RBA, %)a Absolute binding affinities (Ki, nM)a Action
ERα ERβ ERα ERβ
Estradiol E2; 17β-Estradiol 100 100 0.115 (0.04–0.24) 0.15 (0.10–2.08) Estrogen
Estrone E1; 17-Ketoestradiol 16.39 (0.7–60) 6.5 (1.36–52) 0.445 (0.3–1.01) 1.75 (0.35–9.24) Estrogen
Estriol E3; 16α-OH-17β-E2 12.65 (4.03–56) 26 (14.0–44.6) 0.45 (0.35–1.4) 0.7 (0.63–0.7) Estrogen
Estetrol E4; 15α,16α-Di-OH-17β-E2 4.0 3.0 4.9 19 Estrogen
Alfatradiol 17α-Estradiol 20.5 (7–80.1) 8.195 (2–42) 0.2–0.52 0.43–1.2 Metabolite
16-Epiestriol 16β-Hydroxy-17β-estradiol 7.795 (4.94–63) 50 ? ? Metabolite
17-Epiestriol 16α-Hydroxy-17α-estradiol 55.45 (29–103) 79–80 ? ? Metabolite
16,17-Epiestriol 16β-Hydroxy-17α-estradiol 1.0 13 ? ? Metabolite
2-Hydroxyestradiol 2-OH-E2 22 (7–81) 11–35 2.5 1.3 Metabolite
2-Methoxyestradiol 2-MeO-E2 0.0027–2.0 1.0 ? ? Metabolite
4-Hydroxyestradiol 4-OH-E2 13 (8–70) 7–56 1.0 1.9 Metabolite
4-Methoxyestradiol 4-MeO-E2 2.0 1.0 ? ? Metabolite
2-Hydroxyestrone 2-OH-E1 2.0–4.0 0.2–0.4 ? ? Metabolite
2-Methoxyestrone 2-MeO-E1 <0.001–<1 <1 ? ? Metabolite
4-Hydroxyestrone 4-OH-E1 1.0–2.0 1.0 ? ? Metabolite
4-Methoxyestrone 4-MeO-E1 <1 <1 ? ? Metabolite
16α-Hydroxyestrone 16α-OH-E1; 17-Ketoestriol 2.0–6.5 35 ? ? Metabolite
2-Hydroxyestriol 2-OH-E3 2.0 1.0 ? ? Metabolite
4-Methoxyestriol 4-MeO-E3 1.0 1.0 ? ? Metabolite
Estradiol sulfate E2S; Estradiol 3-sulfate <1 <1 ? ? Metabolite
Estradiol disulfate Estradiol 3,17β-disulfate 0.0004 ? ? ? Metabolite
Estradiol 3-glucuronide E2-3G 0.0079 ? ? ? Metabolite
Estradiol 17β-glucuronide E2-17G 0.0015 ? ? ? Metabolite
Estradiol 3-gluc. 17β-sulfate E2-3G-17S 0.0001 ? ? ? Metabolite
Estrone sulfate E1S; Estrone 3-sulfate <1 <1 >10 >10 Metabolite
Estradiol benzoate EB; Estradiol 3-benzoate 10 ? ? ? Estrogen
Estradiol 17β-benzoate E2-17B 11.3 32.6 ? ? Estrogen
Estrone methyl ether Estrone 3-methyl ether 0.145 ? ? ? Estrogen
ent-Estradiol 1-Estradiol 1.31–12.34 9.44–80.07 ? ? Estrogen
Equilin 7-Dehydroestrone 13 (4.0–28.9) 13.0–49 0.79 0.36 Estrogen
Equilenin 6,8-Didehydroestrone 2.0–15 7.0–20 0.64 0.62 Estrogen
17β-Dihydroequilin 7-Dehydro-17β-estradiol 7.9–113 7.9–108 0.09 0.17 Estrogen
17α-Dihydroequilin 7-Dehydro-17α-estradiol 18.6 (18–41) 14–32 0.24 0.57 Estrogen
17β-Dihydroequilenin 6,8-Didehydro-17β-estradiol 35–68 90–100 0.15 0.20 Estrogen
17α-Dihydroequilenin 6,8-Didehydro-17α-estradiol 20 49 0.50 0.37 Estrogen
Δ8-Estradiol 8,9-Dehydro-17β-estradiol 68 72 0.15 0.25 Estrogen
Δ8-Estrone 8,9-Dehydroestrone 19 32 0.52 0.57 Estrogen
Ethinylestradiol EE; 17α-Ethynyl-17β-E2 120.9 (68.8–480) 44.4 (2.0–144) 0.02–0.05 0.29–0.81 Estrogen
Mestranol EE 3-methyl ether ? 2.5 ? ? Estrogen
Moxestrol RU-2858; 11β-Methoxy-EE 35–43 5–20 0.5 2.6 Estrogen
Methylestradiol 17α-Methyl-17β-estradiol 70 44 ? ? Estrogen
Diethylstilbestrol DES; Stilbestrol 129.5 (89.1–468) 219.63 (61.2–295) 0.04 0.05 Estrogen
Hexestrol Dihydrodiethylstilbestrol 153.6 (31–302) 60–234 0.06 0.06 Estrogen
Dienestrol Dehydrostilbestrol 37 (20.4–223) 56–404 0.05 0.03 Estrogen
Benzestrol (B2) – 114 ? ? ? Estrogen
Chlorotrianisene TACE 1.74 ? 15.30 ? Estrogen
Triphenylethylene TPE 0.074 ? ? ? Estrogen
Triphenylbromoethylene TPBE 2.69 ? ? ? Estrogen
Tamoxifen ICI-46,474 3 (0.1–47) 3.33 (0.28–6) 3.4–9.69 2.5 SERM
Afimoxifene 4-Hydroxytamoxifen; 4-OHT 100.1 (1.7–257) 10 (0.98–339) 2.3 (0.1–3.61) 0.04–4.8 SERM
Toremifene 4-Chlorotamoxifen; 4-CT ? ? 7.14–20.3 15.4 SERM
Clomifene MRL-41 25 (19.2–37.2) 12 0.9 1.2 SERM
Cyclofenil F-6066; Sexovid 151–152 243 ? ? SERM
Nafoxidine U-11,000A 30.9–44 16 0.3 0.8 SERM
Raloxifene – 41.2 (7.8–69) 5.34 (0.54–16) 0.188–0.52 20.2 SERM
Arzoxifene LY-353,381 ? ? 0.179 ? SERM
Lasofoxifene CP-336,156 10.2–166 19.0 0.229 ? SERM
Ormeloxifene Centchroman ? ? 0.313 ? SERM
Levormeloxifene 6720-CDRI; NNC-460,020 1.55 1.88 ? ? SERM
Ospemifene Deaminohydroxytoremifene 0.82–2.63 0.59–1.22 ? ? SERM
Bazedoxifene – ? ? 0.053 ? SERM
Etacstil GW-5638 4.30 11.5 ? ? SERM
ICI-164,384 – 63.5 (3.70–97.7) 166 0.2 0.08 Antiestrogen
Fulvestrant ICI-182,780 43.5 (9.4–325) 21.65 (2.05–40.5) 0.42 1.3 Antiestrogen
Propylpyrazoletriol PPT 49 (10.0–89.1) 0.12 0.40 92.8 ERα agonist
16α-LE2 16α-Lactone-17β-estradiol 14.6–57 0.089 0.27 131 ERα agonist
16α-Iodo-E2 16α-Iodo-17β-estradiol 30.2 2.30 ? ? ERα agonist
Methylpiperidinopyrazole MPP 11 0.05 ? ? ERα antagonist
Diarylpropionitrile DPN 0.12–0.25 6.6–18 32.4 1.7 ERβ agonist
8β-VE2 8β-Vinyl-17β-estradiol 0.35 22.0–83 12.9 0.50 ERβ agonist
Prinaberel ERB-041; WAY-202,041 0.27 67–72 ? ? ERβ agonist
ERB-196 WAY-202,196 ? 180 ? ? ERβ agonist
Erteberel SERBA-1; LY-500,307 ? ? 2.68 0.19 ERβ agonist
SERBA-2 – ? ? 14.5 1.54 ERβ agonist
Coumestrol – 9.225 (0.0117–94) 64.125 (0.41–185) 0.14–80.0 0.07–27.0 Xenoestrogen
Genistein – 0.445 (0.0012–16) 33.42 (0.86–87) 2.6–126 0.3–12.8 Xenoestrogen
Equol – 0.2–0.287 0.85 (0.10–2.85) ? ? Xenoestrogen
Daidzein – 0.07 (0.0018–9.3) 0.7865 (0.04–17.1) 2.0 85.3 Xenoestrogen
Biochanin A – 0.04 (0.022–0.15) 0.6225 (0.010–1.2) 174 8.9 Xenoestrogen
Kaempferol – 0.07 (0.029–0.10) 2.2 (0.002–3.00) ? ? Xenoestrogen
Naringenin – 0.0054 (<0.001–0.01) 0.15 (0.11–0.33) ? ? Xenoestrogen
8-Prenylnaringenin 8-PN 4.4 ? ? ? Xenoestrogen
Quercetin – <0.001–0.01 0.002–0.040 ? ? Xenoestrogen
Ipriflavone – <0.01 <0.01 ? ? Xenoestrogen
Miroestrol – 0.39 ? ? ? Xenoestrogen
Deoxymiroestrol – 2.0 ? ? ? Xenoestrogen
β-Sitosterol – <0.001–0.0875 <0.001–0.016 ? ? Xenoestrogen
Resveratrol – <0.001–0.0032 ? ? ? Xenoestrogen
α-Zearalenol – 48 (13–52.5) ? ? ? Xenoestrogen
β-Zearalenol – 0.6 (0.032–13) ? ? ? Xenoestrogen
Zeranol α-Zearalanol 48–111 ? ? ? Xenoestrogen
Taleranol β-Zearalanol 16 (13–17.8) 14 0.8 0.9 Xenoestrogen
Zearalenone ZEN 7.68 (2.04–28) 9.45 (2.43–31.5) ? ? Xenoestrogen
Zearalanone ZAN 0.51 ? ? ? Xenoestrogen
Bisphenol A BPA 0.0315 (0.008–1.0) 0.135 (0.002–4.23) 195 35 Xenoestrogen
Endosulfan EDS <0.001–<0.01 <0.01 ? ? Xenoestrogen
Kepone Chlordecone 0.0069–0.2 ? ? ? Xenoestrogen
o,p'-DDT – 0.0073–0.4 ? ? ? Xenoestrogen
p,p'-DDT – 0.03 ? ? ? Xenoestrogen
Methoxychlor p,p'-Dimethoxy-DDT 0.01 (<0.001–0.02) 0.01–0.13 ? ? Xenoestrogen
HPTE Hydroxychlor; p,p'-OH-DDT 1.2–1.7 ? ? ? Xenoestrogen
Testosterone T; 4-Androstenolone <0.0001–<0.01 <0.002–0.040 >5000 >5000 Androgen
Dihydrotestosterone DHT; 5α-Androstanolone 0.01 (<0.001–0.05) 0.0059–0.17 221–>5000 73–1688 Androgen
Nandrolone 19-Nortestosterone; 19-NT 0.01 0.23 765 53 Androgen
Dehydroepiandrosterone DHEA; Prasterone 0.038 (<0.001–0.04) 0.019–0.07 245–1053 163–515 Androgen
5-Androstenediol A5; Androstenediol 6 17 3.6 0.9 Androgen
4-Androstenediol – 0.5 0.6 23 19 Androgen
4-Androstenedione A4; Androstenedione <0.01 <0.01 >10000 >10000 Androgen
3α-Androstanediol 3α-Adiol 0.07 0.3 260 48 Androgen
3β-Androstanediol 3β-Adiol 3 7 6 2 Androgen
Androstanedione 5α-Androstanedione <0.01 <0.01 >10000 >10000 Androgen
Etiocholanedione 5β-Androstanedione <0.01 <0.01 >10000 >10000 Androgen
Methyltestosterone 17α-Methyltestosterone <0.0001 ? ? ? Androgen
Ethinyl-3α-androstanediol 17α-Ethynyl-3α-adiol 4.0 <0.07 ? ? Estrogen
Ethinyl-3β-androstanediol 17α-Ethynyl-3β-adiol 50 5.6 ? ? Estrogen
Progesterone P4; 4-Pregnenedione <0.001–0.6 <0.001–0.010 ? ? Progestogen
Norethisterone NET; 17α-Ethynyl-19-NT 0.085 (0.0015–<0.1) 0.1 (0.01–0.3) 152 1084 Progestogen
Norethynodrel 5(10)-Norethisterone 0.5 (0.3–0.7) <0.1–0.22 14 53 Progestogen
Tibolone 7α-Methylnorethynodrel 0.5 (0.45–2.0) 0.2–0.076 ? ? Progestogen
Δ4-Tibolone 7α-Methylnorethisterone 0.069–<0.1 0.027–<0.1 ? ? Progestogen
3α-Hydroxytibolone – 2.5 (1.06–5.0) 0.6–0.8 ? ? Progestogen
3β-Hydroxytibolone – 1.6 (0.75–1.9) 0.070–0.1 ? ? Progestogen
Footnotes: a = (1) Binding affinity values are of the format "median (range)" (# (#–#)), "range" (#–#), or "value" (#) depending on the values available. The full sets of values within the ranges can be found in the Wiki code. (2) Binding affinities were determined via displacement studies in a variety of in-vitro systems with labeled estradiol and human ERα and ERβ proteins (except the ERβ values from Kuiper et al. (1997), which are rat ERβ). Sources: See template page.

Binding and functional selectivity

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The ER's helix 12 domain plays a crucial role in determining interactions with coactivators and corepressors and, therefore, the respective agonist or antagonist effect of the ligand.[39][40]

Different ligands may differ in their affinity for alpha and beta isoforms of the estrogen receptor:

Subtype selective estrogen receptor modulators preferentially bind to either the α- or the β-subtype of the receptor. In addition, the different estrogen receptor combinations may respond differently to various ligands, which may translate into tissue selective agonistic and antagonistic effects.[42] The ratio of α- to β- subtype concentration has been proposed to play a role in certain diseases.[43]

The concept of selective estrogen receptor modulators is based on the ability to promote ER interactions with different proteins such as transcriptional coactivator or corepressors. Furthermore, the ratio of coactivator to corepressor protein varies in different tissues.[44] As a consequence, the same ligand may be an agonist in some tissue (where coactivators predominate) while antagonistic in other tissues (where corepressors dominate). Tamoxifen, for example, is an antagonist in breast and is, therefore, used as a breast cancer treatment[25] but an ER agonist in bone (thereby preventing osteoporosis) and a partial agonist in the endometrium (increasing the risk of uterine cancer).

Discovery

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Estrogen receptors were first identified by Elwood V. Jensen at the University of Chicago in 1958,[45][46] for which Jensen was awarded the Lasker Award.[47] The gene for a second estrogen receptor (ERβ) was identified in 1996 by Kuiper et al. in rat prostate and ovary using degenerate ERalpha primers.[48]

See also

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References

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  1. ^ Dahlman-Wright K, Cavailles V, Fuqua SA, Jordan VC, Katzenellenbogen JA, Korach KS, et al. (December 2006). "International Union of Pharmacology. LXIV. Estrogen receptors". Pharmacological Reviews. 58 (4): 773–781. doi:10.1124/pr.58.4.8. PMID 17132854. S2CID 45996586.
  2. ^ a b Levin ER (August 2005). "Integration of the extranuclear and nuclear actions of estrogen". Molecular Endocrinology. 19 (8): 1951–1959. doi:10.1210/me.2004-0390. PMC 1249516. PMID 15705661.
  3. ^ Li X, Huang J, Yi P, Bambara RA, Hilf R, Muyan M (September 2004). "Single-chain estrogen receptors (ERs) reveal that the ERalpha/beta heterodimer emulates functions of the ERalpha dimer in genomic estrogen signaling pathways". Molecular and Cellular Biology. 24 (17): 7681–7694. doi:10.1128/MCB.24.17.7681-7694.2004. PMC 506997. PMID 15314175.
  4. ^ Nilsson S, Mäkelä S, Treuter E, Tujague M, Thomsen J, Andersson G, et al. (October 2001). "Mechanisms of estrogen action". Physiological Reviews. 81 (4): 1535–1565. doi:10.1152/physrev.2001.81.4.1535. PMID 11581496. S2CID 10223568.
  5. ^ Leung YK, Mak P, Hassan S, Ho SM (August 2006). "Estrogen receptor (ER)-beta isoforms: a key to understanding ER-beta signaling". Proceedings of the National Academy of Sciences of the United States of America. 103 (35): 13162–13167. Bibcode:2006PNAS..10313162L. doi:10.1073/pnas.0605676103. PMC 1552044. PMID 16938840.
  6. ^ Hawkins MB, Thornton JW, Crews D, Skipper JK, Dotte A, Thomas P (September 2000). "Identification of a third distinct estrogen receptor and reclassification of estrogen receptors in teleosts". Proceedings of the National Academy of Sciences of the United States of America. 97 (20): 10751–10756. Bibcode:2000PNAS...9710751H. doi:10.1073/pnas.97.20.10751. PMC 27095. PMID 11005855.
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