Biology:Estrogen receptor

From HandWiki
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
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

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).

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

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

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
Estrogen and estrogen related receptor C-terminal domain
Identifiers
SymbolESR1_C
PfamPF12743

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]


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

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

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

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

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

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

Cancer

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 or radio-ligand binding assay which quantifies these receptor proteins. Two hypotheses have been proposed to explain why this causes tumorigenesis, and the available evidence suggests that both mechanisms contribute:

  • First, binding of estrogen to the ER stimulates proliferation of mammary cells, with the resulting increase in cell division and DNA replication, leading to mutations.
  • Second, estrogen metabolism produces genotoxic waste.

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 standardized ER tests as developed by New England Nuclear and Wittliff,[26] 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.[27]

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.[28] Another SERM, raloxifene, has been used as a preventive chemotherapy for women judged to have a high risk of developing breast cancer.[29] 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.[30] 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.[31]

Menopause

The metabolic effects of estrogen in postmenopausal women has been linked to the genetic polymorphism of estrogen receptor beta (ER-β).[32]

Aging

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

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.[33] Obesity was also observed in estrogen deficient female mice lacking the follicle-stimulating hormone receptor.[34] The effect of low estrogen on increased obesity has been linked to estrogen receptor alpha.[35]

SERMs for other treatment purposes

SERMs are also being studied for the treatment of uterine fibroids[36] and endometriosis.[37] 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.[36] It is also not clear if SERMs is effective for treating endometriosis.[37]

Estrogen insensitivity syndrome

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 analogous 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 inherited, 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.[38][39]

Ligands

Agonists

Mixed (agonist and antagonist mode of action)

Antagonists

Affinities

v · d · e 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 Script error: The function "median" does not exist. (0.04–0.24) Script error: The function "median" does not exist. (0.10–2.08) Estrogen
Estrone E1; 17-Ketoestradiol Script error: The function "median" does not exist. (0.7–60) Script error: The function "median" does not exist. (1.36–52) Script error: The function "median" does not exist. (0.3–1.01) Script error: The function "median" does not exist. (0.35–9.24) Estrogen
Estriol E3; 16α-OH-17β-E2 Script error: The function "median" does not exist. (4.03–56) Script error: The function "median" does not exist. (14.0–44.6) Script error: The function "median" does not exist. (0.35–1.4) Script error: The function "median" does not exist. (0.63–0.7) Estrogen
Estetrol E4; 15α,16α-Di-OH-17β-E2 4.0 3.0 4.9 19 Estrogen
Alfatradiol 17α-Estradiol Script error: The function "median" does not exist. (7–80.1) Script error: The function "median" does not exist. (2–42) 0.2–0.52 0.43–1.2 Metabolite
16-Epiestriol 16β-Hydroxy-17β-estradiol Script error: The function "median" does not exist. (4.94–63) 50 ? ? Metabolite
17-Epiestriol 16α-Hydroxy-17α-estradiol Script error: The function "median" does not exist. (29–103) 79–80 ? ? Metabolite
16,17-Epiestriol 16β-Hydroxy-17α-estradiol 1.0 13 ? ? Metabolite
2-Hydroxyestradiol 2-OH-E2 Script error: The function "median" does not exist. (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 Script error: The function "median" does not exist. (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 Script error: The function "median" does not exist. (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 Script error: The function "median" does not exist. (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 Script error: The function "median" does not exist. (68.8–480) Script error: The function "median" does not exist. (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 Script error: The function "median" does not exist. (89.1–468) Script error: The function "median" does not exist. (61.2–295) 0.04 0.05 Estrogen
Hexestrol Dihydrodiethylstilbestrol Script error: The function "median" does not exist. (31–302) 60–234 0.06 0.06 Estrogen
Dienestrol Dehydrostilbestrol Script error: The function "median" does not exist. (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 Script error: The function "median" does not exist. (0.1–47) Script error: The function "median" does not exist. (0.28–6) 3.4–9.69 2.5 SERM
Afimoxifene 4-Hydroxytamoxifen; 4-OHT Script error: The function "median" does not exist. (1.7–257) Script error: The function "median" does not exist. (0.98–339) Script error: The function "median" does not exist. (0.1–3.61) 0.04–4.8 SERM
Toremifene 4-Chlorotamoxifen; 4-CT ? ? 7.14–20.3 15.4 SERM
Clomifene MRL-41 Script error: The function "median" does not exist. (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 – Script error: The function "median" does not exist. (7.8–69) Script error: The function "median" does not exist. (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 2.63 1.22 ? ? SERM
Bazedoxifene – ? ? 0.053 ? SERM
Etacstil GW-5638 4.30 11.5 ? ? SERM
ICI-164,384 – Script error: The function "median" does not exist. (3.70–97.7) 166 0.2 0.08 Antiestrogen
Fulvestrant ICI-182,780 Script error: The function "median" does not exist. (9.4–325) Script error: The function "median" does not exist. (2.05–40.5) 0.42 1.3 Antiestrogen
Propylpyrazoletriol PPT Script error: The function "median" does not exist. (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 – Script error: The function "median" does not exist. (0.0117–94) Script error: The function "median" does not exist. (0.41–185) 0.14–80.0 0.07–27.0 Xenoestrogen
Genistein – Script error: The function "median" does not exist. (0.0012–16) Script error: The function "median" does not exist. (0.86–87) 2.6–126 0.3–12.8 Xenoestrogen
Equol – 0.2–0.287 Script error: The function "median" does not exist. (0.10–2.85) ? ? Xenoestrogen
Daidzein – Script error: The function "median" does not exist. (0.0018–9.3) Script error: The function "median" does not exist. (0.04–17.1) 2.0 85.3 Xenoestrogen
Biochanin A – Script error: The function "median" does not exist. (0.022–0.15) Script error: The function "median" does not exist. (0.010–1.2) 174 8.9 Xenoestrogen
Kaempferol – Script error: The function "median" does not exist. (0.029–0.10) Script error: The function "median" does not exist. (0.002–3.00) ? ? Xenoestrogen
Naringenin – Script error: The function "median" does not exist. (<0.001–0.01) Script error: The function "median" does not exist. (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 – Script error: The function "median" does not exist. (13–52.5) ? ? ? Xenoestrogen
β-Zearalenol – Script error: The function "median" does not exist. (0.032–13) ? ? ? Xenoestrogen
Zeranol α-Zearalanol 48–111 ? ? ? Xenoestrogen
Taleranol β-Zearalanol Script error: The function "median" does not exist. (13–17.8) 14 0.8 0.9 Xenoestrogen
Zearalenone ZEN Script error: The function "median" does not exist. (2.04–28) Script error: The function "median" does not exist. (2.43–31.5) ? ? Xenoestrogen
Zearalanone ZAN 0.51 ? ? ? Xenoestrogen
Bisphenol A BPA Script error: The function "median" does not exist. (0.008–1.0) Script error: The function "median" does not exist. (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 – Script error: The function "median" does not exist. ? ? ? Xenoestrogen
Methoxychlor p,p'-Dimethoxy-DDT Script error: The function "median" does not exist. (<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 Script error: The function "median" does not exist. (<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 Script error: The function "median" does not exist. (<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 Script error: The function "median" does not exist. (0.0015–<0.1) Script error: The function "median" does not exist. (0.01–0.3) 152 1084 Progestogen
Norethynodrel 5(10)-Norethisterone Script error: The function "median" does not exist. (0.3–0.7) <0.1–0.22 14 53 Progestogen
Tibolone 7α-Methylnorethynodrel Script error: The function "median" does not exist. (0.45–2.0) 0.2–0.076 ? ? Progestogen
Δ4-Tibolone 7α-Methylnorethisterone 0.069–<0.1 0.027–<0.1 ? ? Progestogen
3α-Hydroxytibolone – Script error: The function "median" does not exist. (1.06–5.0) 0.6–0.8 ? ? Progestogen
3β-Hydroxytibolone – Script error: The function "median" does not exist. (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

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.[40][41]

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.[43] The ratio of α- to β- subtype concentration has been proposed to play a role in certain diseases.[44]

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.[45] 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

Estrogen receptors were first identified by Elwood V. Jensen at the University of Chicago in 1958,[46][47] for which Jensen was awarded the Lasker Award.[48] 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.[49]

See also

References

  1. ↑ "International Union of Pharmacology. LXIV. Estrogen receptors". Pharmacological Reviews 58 (4): 773–781. December 2006. doi:10.1124/pr.58.4.8. PMID 17132854. 
  2. ↑ 2.0 2.1 "Integration of the extranuclear and nuclear actions of estrogen". Molecular Endocrinology 19 (8): 1951–1959. August 2005. doi:10.1210/me.2004-0390. PMID 15705661. 
  3. ↑ "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. September 2004. doi:10.1128/MCB.24.17.7681-7694.2004. PMID 15314175. 
  4. ↑ "Mechanisms of estrogen action". Physiological Reviews 81 (4): 1535–1565. October 2001. doi:10.1152/physrev.2001.81.4.1535. PMID 11581496. 
  5. ↑ "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. August 2006. doi:10.1073/pnas.0605676103. PMID 16938840. Bibcode: 2006PNAS..10313162L. 
  6. ↑ "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. September 2000. doi:10.1073/pnas.97.20.10751. PMID 11005855. Bibcode: 2000PNAS...9710751H. 
  7. ↑ "Tissue distribution and quantitative analysis of estrogen receptor-alpha (ERalpha) and estrogen receptor-beta (ERbeta) messenger ribonucleic acid in the wild-type and ERalpha-knockout mouse". Endocrinology 138 (11): 4613–4621. November 1997. doi:10.1210/en.138.11.4613. PMID 9348186. 
  8. ↑ 8.0 8.1 "Caloric restriction reduces cell loss and maintains estrogen receptor-alpha immunoreactivity in the pre-optic hypothalamus of female B6D2F1 mice". Neuro Endocrinology Letters 26 (3): 197–203. June 2005. PMID 15990721. http://www.nel.edu/pdf_/26_3/260305A01_15990721_Yaghmaie_.pdf. 
  9. ↑ "Estrogen in the adult male reproductive tract: a review". Reproductive Biology and Endocrinology 1 (52). July 2003. doi:10.1186/1477-7827-1-52. PMID 12904263. 
  10. ↑ "Estrogenic hormone action in the heart: regulatory network and function". Cardiovascular Research 53 (3): 709–719. February 2002. doi:10.1016/S0008-6363(01)00526-0. PMID 11861041. 
  11. ↑ "Direct visualization of the human estrogen receptor alpha reveals a role for ligand in the nuclear distribution of the receptor". Molecular Biology of the Cell 10 (2): 471–486. February 1999. doi:10.1091/mbc.10.2.471. PMID 9950689. 
  12. ↑ "Coexpression of multiple estrogen receptor variant messenger RNAs in normal and neoplastic breast tissues and in MCF-7 cells". Cancer Research 55 (10): 2158–2165. May 1995. PMID 7743517. 
  13. ↑ "Molecular mechanism of estrogen-estrogen receptor signaling". Reproductive Medicine and Biology 16 (1): 4–20. January 2017. doi:10.1002/rmb2.12006. PMID 29259445. 
  14. ↑ "Estrogen receptor signaling mechanisms". Advances in Protein Chemistry and Structural Biology 116: 135–170. 2019. doi:10.1016/bs.apcsb.2019.01.001. ISBN 978-0-12-815561-5. PMID 31036290. 
  15. ↑ 15.0 15.1 15.2 "International Union of Pharmacology. LXIV. Estrogen receptors". Pharmacological Reviews 58 (4): 773–781. December 2006. doi:10.1124/pr.58.4.8. PMID 17132854. 
  16. ↑ "Integration of the extranuclear and nuclear actions of estrogen". Molecular Endocrinology 19 (8): 1951–1959. August 2005. doi:10.1210/me.2004-0390. PMID 15705661. 
  17. ↑ "LKB1 catalytic activity contributes to estrogen receptor alpha signaling". Molecular Biology of the Cell 20 (11): 2785–2795. June 2009. doi:10.1091/MBC.E08-11-1138. PMID 19369417. 
  18. ↑ "Direct acetylation of the estrogen receptor alpha hinge region by p300 regulates transactivation and hormone sensitivity". The Journal of Biological Chemistry 276 (21): 18375–83. May 2001. doi:10.1074/jbc.M100800200. PMID 11279135. 
  19. ↑ 19.0 19.1 "Membrane estrogen receptor-alpha levels in MCF-7 breast cancer cells predict cAMP and proliferation responses". Breast Cancer Research 7 (1): R101–R112. 2005. doi:10.1186/bcr958. PMID 15642158. 
  20. ↑ "Estrogen receptor-dependent activation of AP-1 via non-genomic signalling". Nuclear Receptor 2 (1). June 2004. doi:10.1186/1478-1336-2-3. PMID 15196329. 
  21. ↑ "Striatin assembles a membrane signaling complex necessary for rapid, nongenomic activation of endothelial NO synthase by estrogen receptor alpha". Proceedings of the National Academy of Sciences of the United States of America 101 (49): 17126–17131. December 2004. doi:10.1073/pnas.0407492101. PMID 15569929. Bibcode: 2004PNAS..10117126L. 
  22. ↑ "Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase". Science 270 (5241): 1491–1494. December 1995. doi:10.1126/science.270.5241.1491. PMID 7491495. Bibcode: 1995Sci...270.1491K. 
  23. ↑ "GPR30: A G protein-coupled receptor for estrogen". Molecular and Cellular Endocrinology 265-266: 138–142. February 2007. doi:10.1016/j.mce.2006.12.010. PMID 17222505. 
  24. ↑ "G protein-coupled receptor 30 localizes to the endoplasmic reticulum and is not activated by estradiol". Endocrinology 149 (10): 4846–4856. October 2008. doi:10.1210/en.2008-0269. PMID 18566127. 
  25. ↑ 25.0 25.1 "Estrogen receptors and human disease". The Journal of Clinical Investigation 116 (3): 561–570. March 2006. doi:10.1172/JCI27987. PMID 16511588. 
  26. ↑ Fisher, B., Redmond, C., Brown, A., Wickerham, D. L., Wolmark, N., Allegra, J. C., Escher, G., Lippman, M., Savlov, E., Wittliff, J. L. and Fisher, E. R. et al. Influence of Tumor Estrogen and Progesterone Receptor Levels on the Response to Tamoxifen and Chemotherapy in Primary Breast Cancer. J. Clin. Oncol., 1:227-241, 1983. https://pubmed.ncbi.nlm.nih.gov/6366135/
  27. ↑ "Evaluation of an estrogen receptor-beta agonist in animal models of human disease". Endocrinology 144 (10): 4241–4249. October 2003. doi:10.1210/en.2003-0550. PMID 14500559. 
  28. ↑ "Tamoxifen ("Nolvadex"): a review". Cancer Treatment Reviews 28 (4): 165–180. August 2002. doi:10.1016/s0305-7372(02)00036-1. PMID 12363457. 
  29. ↑ "Selective estrogen-receptor modulators for primary prevention of breast cancer". Journal of Clinical Oncology 23 (8): 1644–1655. March 2005. doi:10.1200/JCO.2005.11.005. PMID 15755972. 
  30. ↑ "The search for ESR1 mutations in breast cancer". Nature Genetics 45 (12): 1415–1416. December 2013. doi:10.1038/ng.2831. PMID 24270445. 
  31. ↑ "Endocrine-therapy-resistant ESR1 variants revealed by genomic characterization of breast-cancer-derived xenografts". Cell Reports 4 (6): 1116–1130. September 2013. doi:10.1016/j.celrep.2013.08.022. PMID 24055055. 
  32. ↑ "Effect of estrogen receptor β A1730G polymorphism on ABCA1 gene expression response to postmenopausal hormone replacement therapy". Genetic Testing and Molecular Biomarkers 15 (1–2): 11–15. 2011. doi:10.1089/gtmb.2010.0106. PMID 21117950. 
  33. ↑ "The aromatase knockout mouse presents with a sexually dimorphic disruption to cholesterol homeostasis". Endocrinology 144 (9): 3895–3903. September 2003. doi:10.1210/en.2003-0244. PMID 12933663. 
  34. ↑ "Estrogen deficiency, obesity, and skeletal abnormalities in follicle-stimulating hormone receptor knockout (FORKO) female mice". Endocrinology 141 (11): 4295–4308. November 2000. doi:10.1210/endo.141.11.7765. PMID 11089565. 
  35. ↑ "Obesity and disturbed lipoprotein profile in estrogen receptor-alpha-deficient male mice". Biochemical and Biophysical Research Communications 278 (3): 640–645. November 2000. doi:10.1006/bbrc.2000.3827. PMID 11095962. 
  36. ↑ 36.0 36.1 "Selective estrogen receptor modulators (SERMs) for uterine leiomyomas". The Cochrane Database of Systematic Reviews 2012 (10). October 2012. doi:10.1002/14651858.CD005287.pub4. PMID 23076912. 
  37. ↑ 37.0 37.1 "Selective oestrogen receptor modulators (SERMs) for endometriosis". The Cochrane Database of Systematic Reviews 2021 (5). May 2021. doi:10.1002/14651858.CD011169.pub2. PMID 33973648. 
  38. ↑ Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. 24 January 2012. pp. 1392–. ISBN 978-1-60913-345-0. https://books.google.com/books?id=Sd6ot9ul-bUC&pg=PA1392. 
  39. ↑ "Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man". The New England Journal of Medicine 331 (16): 1056–1061. October 1994. doi:10.1056/NEJM199410203311604. PMID 8090165. 
  40. ↑ "Structure-function relationship of estrogen receptor alpha and beta: impact on human health". Molecular Aspects of Medicine 27 (4): 299–402. August 2006. doi:10.1016/j.mam.2006.07.001. PMID 16914190. 
  41. ↑ "Nuclear receptor ligand-binding domains: three-dimensional structures, molecular interactions and pharmacological implications". Trends in Pharmacological Sciences 21 (10): 381–388. October 2000. doi:10.1016/S0165-6147(00)01548-0. PMID 11050318. 
  42. ↑ 42.0 42.1 42.2 "Quantitative structure-activity relationship of various endogenous estrogen metabolites for human estrogen receptor alpha and beta subtypes: Insights into the structural determinants favoring a differential subtype binding". Endocrinology 147 (9): 4132–4150. September 2006. doi:10.1210/en.2006-0113. PMID 16728493. 
  43. ↑ "Differential effects of estrogen receptor antagonists on pituitary lactotroph proliferation and prolactin release". Molecular and Cellular Endocrinology 239 (1–2): 27–36. July 2005. doi:10.1016/j.mce.2005.04.008. PMID 15950373. 
  44. ↑ "Estrogen receptor alpha and beta in uterine fibroids: a basis for altered estrogen responsiveness". Fertility and Sterility 90 (5): 1878–1885. November 2008. doi:10.1016/j.fertnstert.2007.09.019. PMID 18166184. 
  45. ↑ "Molecular determinants for the tissue specificity of SERMs". Science 295 (5564): 2465–2468. March 2002. doi:10.1126/science.1068537. PMID 11923541. Bibcode: 2002Sci...295.2465S. 
  46. ↑ "The estrogen receptor: a model for molecular medicine" (abstract). Clinical Cancer Research 9 (6): 1980–1989. June 2003. PMID 12796359. http://clincancerres.aacrjournals.org/cgi/content/abstract/9/6/1980. 
  47. ↑ "A conversation with Elwood Jensen. Interview by David D. Moore". Annual Review of Physiology 74: 1–11. 2011. doi:10.1146/annurev-physiol-020911-153327. PMID 21888507. 
  48. ↑ "UC Scientist Wins 'American Nobel' Research Award". University of Cincinnati press release. 2004. http://www.uc.edu/news/NR.asp?id=1993. 
  49. ↑ "Cloning of a novel receptor expressed in rat prostate and ovary". Proceedings of the National Academy of Sciences of the United States of America 93 (12): 5925–5930. June 1996. doi:10.1073/pnas.93.12.5925. PMID 8650195. 



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