estrogen receptor 1 (ER-alpha)
A dimer of the ligand-binding region of ERα (PDB rendering based on3erd​).
Identifiers
Symbol	ESR1
Alt. symbols	ER-α, NR3A1
NCBI gene	2099
HGNC	3467
OMIM	133430
PDB	1ERE
RefSeq	NM_000125
UniProt	P03372
Other data
Locus	Chr. 6q24-q27
Search for Structures Swiss-model Domains InterPro

estrogen receptor 2 (ER-beta)
A dimer of the ligand-binding region of ERβ (PDB rendering based on1u3s​).
Identifiers
Symbol	ESR2
Alt. symbols	ER-β, NR3A2
NCBI gene	2100
HGNC	3468
OMIM	601663
PDB	1QKM
RefSeq	NM_001040275
UniProt	Q92731
Other data
Locus	Chr. 14q21-q22
Search for Structures Swiss-model Domains InterPro

Estrogen receptors (ERs) areproteins found incells that function asreceptors for thehormoneestrogen (17β-estradiol).^[1] There are two main classes of ERs. The first includes theintracellular estrogen receptors, namelyERα andERβ, which belong to thenuclear receptor family. The second class consists ofmembrane estrogen receptors (mERs), such asGPER (GPR30),ER-X, andG_q-mER, which are primarilyG protein-coupled receptors. This article focuses on the nuclear estrogen receptors (ERα and ERβ).

Upon activation by estrogen, intracellular ERs undergotranslocation to the nucleus where they bind to specific DNA sequences. As DNA-bindingtranscription 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 ofsteroid hormone receptors, which arehormone receptors forsex steroids. Along withandrogen receptors (ARs) andprogesterone receptors (PRs), ERs play crucial roles in regulatingsexual maturation andgestation. These receptors mediate the effects of their respective hormones, contributing to the development and maintenance ofreproductive functions andsecondary sexual characteristics.

In humans, the two forms of the estrogen receptor are encoded by differentgenes,ESR1 andESR2 on the sixth and fourteenthchromosome (6q25.1 and 14q23.2), respectively.

There are two different forms of the estrogen receptor, usually referred to asα andβ, each encoded by a separate gene (ESR1 andESR2, respectively). Hormone-activated estrogen receptors formdimers, 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 fivedomains designated A/B through F (listed from the N- to C-terminus;amino acid sequence numbers refer to human ER).^{[citation needed]}

TheN-terminal A/B domain is able totransactivate gene transcription in the absence of boundligand (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 theDNA-binding domain, binds to estrogenresponse 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 forcoactivator andcorepressor proteins. The E-domain in the presence of bound ligand is able to activate gene transcription. TheC-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]

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

• TheERα is found inendometrium,breast cancer cells, ovarian stromal cells, and thehypothalamus.^[8] In males,ERα protein is found in the epithelium of theefferent ducts.^[9]
• The expression of theERβ protein has been documented in ovariangranulosa cells,kidney,brain,bone,heart,^[10]lungs,intestinal mucosa,prostate, andendothelial cells.

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]

Since estrogen is asteroidal hormone, it can readily diffuse through thephospholipid membranes of cells due to itslipophilic 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]

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 ashormone response elements, initiating the process ofgene regulation.

The DNA/receptor complex then recruits other proteins responsible fortranscription of downstream DNA into mRNA and ultimately protein, resulting in changes in cell function.^[15] Estrogen receptors are also present within thecell nucleus, and both estrogen receptor subtypes (ERα and ERβ) contain aDNA-bindingdomain, allowing them to function astranscription factors regulatingprotein production.^[16]

The receptor also interacts with transcription factors such asactivator protein 1 andSp-1 to promote transcription, via several coactivators includingPELP-1.^[15]Tumor suppressorkinaseLKB1 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]

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

Some ERs interact with cell membranes by binding tocaveolin-1 and forming complexes withG proteins,striatin, receptortyrosine kinases (e.g.,EGFR andIGF-1), and non-receptor tyrosine kinases (e.g.,Src).^[2][19] Membrane-bound ERs associated with striatin can increase levels ofCa²⁺ andnitric oxide (NO).^[21] Interactions with receptor tyrosine kinases trigger signaling to the nucleus via themitogen-activated protein kinase (MAPK/ERK) andphosphoinositide 3-kinase (Pl3K/AKT) pathways.^[22]

Glycogen synthase kinase-3 (GSK)-3β inhibits nuclear ER transcription by preventingphosphorylation ofserine 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 viarsk.

17β-Estradiol has been shown to activate theG protein-coupled receptorGPR30.^[23] However, the subcellular localization and precise role of this receptor remain controversial.^[24]

Estrogen receptors are over-expressed in around 70% ofbreast cancer cases, referred to as "ER-positive", and can be demonstrated in such tissues usingimmunohistochemistry orradio-ligand binding assay which quantifies thesereceptor proteins. Two hypotheses have been proposed to explain why this causestumorigenesis, and the available evidence suggests that both mechanisms contribute:

• First, binding of estrogen to the ER stimulates proliferation ofmammary cells, with the resulting increase incell division andDNA replication, leading to mutations.
• Second, estrogen metabolism producesgenotoxic waste.

The result of both processes is disruption ofcell cycle,apoptosis andDNA 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 theESR1 gene have been identified (withsingle-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 andWittliff,^[26] have also been implicated inbreast cancer,ovarian cancer,colon cancer,prostate cancer, andendometrial 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 involvesselective estrogen receptor modulators (SERMS), such astamoxifen, which behave as ER antagonists in breast tissue, oraromatase inhibitors, such asanastrozole. 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 onESR1 that are drivers for resistance, and promote the agonist conformation of ERα without the boundligand. Such constitutive, estrogen-independent activity is driven by specific mutations, such as the D538G or Y537S/C/N mutations, in the ligand binding domain ofESR1 and promote cell proliferation and tumor progression without hormone stimulation.^[31]

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

Studies in female mice have shown that estrogen receptor-alpha declines in the pre-optichypothalamus as they grow old. Female mice that were given acalorically 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]

A dramatic demonstration of the importance of estrogens in the regulation of fat deposition comes fromtransgenic mice that were genetically engineered to lack a functionalaromatase gene. These mice have very low levels of estrogen and are obese.^[33] Obesity was also observed in estrogen deficient female mice lacking thefollicle-stimulating hormone receptor.^[34] The effect of low estrogen on increased obesity has been linked to estrogen receptor alpha.^[35]

SERMs are also being studied for the treatment ofuterine fibroids^[36] andendometriosis.^[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 is a rareintersex condition with 5 reported cases, in which estrogen receptors do not function. Thephenotype results in extensivemasculinization. Unlikeandrogen insensitivity syndrome, EIS does not result in phenotypesex reversal. It is incredibly rare and is analogous to the AIS, and forms ofadrenal hyperplasia. The reason why AIS is common and EIS is exceptionally rare is that XX AIS does not result ininfertility, and therefore can bematernally inherited, while EIS always results in infertility regardless ofkaryotype. Anegative feedback loop between theendocrine system also occurs in EIS, in which thegonads produce markedly higher levels ofestrogen for individuals with EIS (119–272 pg/mL XY and 750–3,500 pg/mL XX, seeaverage levels) however nofeminizing effects occur.^[38][39]

• Endogenousestrogens (e.g.,estradiol,estrone,estriol,estetrol)
• Naturalestrogens (e.g.,conjugated estrogens)
• Syntheticestrogens (e.g.,ethinylestradiol,diethylstilbestrol)

• Phytoestrogens (e.g.,coumestrol,daidzein,genistein,miroestrol)
• Selective estrogen receptor modulators (e.g.,tamoxifen,clomifene,raloxifene)

• Antiestrogens (e.g.,fulvestrant,ICI-164384,ethamoxytriphetol)

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]

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

• estradiol binds equally well to both receptors^[42]
• estrone, andraloxifene bind preferentially to the alpha receptor^[42]
• estriol, andgenistein to the beta receptor^[42]

Subtypeselective 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 astranscriptionalcoactivator orcorepressors. 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 inbreast and is, therefore, used as abreast cancer treatment^[25] but an ER agonist inbone (thereby preventingosteoporosis) and a partial agonist in theendometrium (increasing the risk ofuterine cancer).

Estrogen receptors were first identified byElwood V. Jensen at theUniversity of Chicago in 1958,^[46][47] for which Jensen was awarded theLasker 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]

• Membrane estrogen receptor
• Estrogen insensitivity syndrome
• Aromatase deficiency
• Aromatase excess syndrome

• Estrogen Receptors at the U.S. National Library of MedicineMedical Subject Headings (MeSH)
• Goodsell DS (September 2003)."Estrogen Receptor".Protein Data Bank, Research Collaboratory for Structural Bioinformatics (RCSB). Archived fromthe original on March 11, 2006. Retrieved2008-03-15.

• Genes on human chromosome 6
• Genes on human chromosome 14
• Human female endocrine system
• Nuclear receptors

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