Editing Estrogen receptor

{{Short description|Proteins activated by the hormone estrogen}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{infobox protein
| Name = [[estrogen receptor alpha|estrogen receptor 1]] (ER-alpha)
| caption =A dimer of the ligand-binding region of ERα ([[Protein Data Bank|PDB]] rendering based on {{PDB2|3erd}}).
| image =PBB_Protein_ESR1_image.png
| width =
| HGNCid = 3467
| Symbol = [[estrogen receptor alpha|ESR1]]
| AltSymbols = ER-α, NR3A1
| EntrezGene = 2099
| OMIM = 133430
| RefSeq = NM_000125
| UniProt = P03372
| PDB = 1ERE
| ECnumber =
| Chromosome = 6
| Arm = q
| Band = 24
| LocusSupplementaryData = -q27
}}
{{infobox protein
| Name = [[estrogen receptor beta|estrogen receptor 2]] (ER-beta)
| caption = A dimer of the ligand-binding region of ERβ ([[Protein Data Bank|PDB]] rendering based on {{PDB2|1u3s}}).
| image = Estrogen receptor beta 1U3S.png
| width = 200
| HGNCid = 3468
| Symbol = [[ESR2]]
| AltSymbols = ER-β, NR3A2
| EntrezGene = 2100
| OMIM = 601663
| RefSeq = NM_001040275
| UniProt = Q92731
| PDB = 1QKM
| ECnumber =
| Chromosome = 14
| Arm = q
| Band = 21
| LocusSupplementaryData = -q22
}}

'''Estrogen receptors''' ('''ERs''') are [[proteins]] found in [[cell (biology)|cells]] that function as [[receptor (biochemistry)|receptors]] for the [[hormone]] [[estrogen]] ([[17β-estradiol]]).<ref name="pmid17132854">{{cite journal | vauthors = Dahlman-Wright K, Cavailles V, Fuqua SA, Jordan VC, Katzenellenbogen JA, Korach KS, Maggi A, Muramatsu M, Parker MG, Gustafsson JA | title = International Union of Pharmacology. LXIV. Estrogen receptors | journal = Pharmacological Reviews | volume = 58 | issue = 4 | pages = 773–781 | date = December 2006 | pmid = 17132854 | doi = 10.1124/pr.58.4.8 | s2cid = 45996586 }}</ref> 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 receptor]]s (mERs), such as [[GPER]] (GPR30), [[ER-X]], and [[Gq-mER|G<sub>q</sub>-mER]], which are primarily [[G protein-coupled receptor]]s. This article focuses on the nuclear estrogen receptors (ERα and ERβ).

Upon activation by estrogen, intracellular ERs undergo [[protein targeting|translocation]] to the nucleus where they bind to specific DNA sequences. As DNA-binding [[transcription factor]]s, they regulate the activity of various genes. However, ERs also exhibit functions that are independent of their DNA-binding capacity.<ref name="pmid15705661">{{cite journal | vauthors = Levin ER | title = Integration of the extranuclear and nuclear actions of estrogen | journal = Molecular Endocrinology | volume = 19 | issue = 8 | pages = 1951–1959 | date = August 2005 | pmid = 15705661 | pmc = 1249516 | doi = 10.1210/me.2004-0390 }}</ref> These non-genomic actions contribute to the diverse effects of estrogen signaling in cells.

Estrogen receptors (ERs) belong to the family of [[steroid hormone receptor]]s, which are [[hormone receptor]]s for [[sex steroid]]s. Along with [[androgen receptor]]s (ARs) and [[progesterone receptor]]s (PRs), ERs play crucial roles in regulating [[sexual maturity|sexual maturation]] and [[gestation]]. These receptors mediate the effects of their respective hormones, contributing to the development and maintenance of [[reproduction|reproductive function]]s and [[secondary sexual characteristic]]s.

== Genes ==
In humans, the two forms of the estrogen receptor are encoded by different [[gene]]s, {{gene|ESR1}} and {{gene|ESR2}} on the sixth and fourteenth [[chromosome]] (6q25.1 and 14q23.2), respectively.

== Structure ==
[[Image:Er domains.svg|thumb|left|400px|The domain structures of ERα and ERβ, including some of the known phosphorylation sites involved in ligand-independent regulation.]]

{{Infobox protein family
| Symbol = Oest_recep
| Name = Estrogen receptor alpha<br />N-terminal AF1 domain
| image =
| width =
| caption =
| Pfam= PF02159
| InterPro= IPR001292
| SMART=
| Prosite =        
| SCOP = 1hcp
| TCDB =
| OPM family=
| OPM protein=
| PDB=
}}
{{Infobox protein family
| Symbol = ESR1_C
| Name = Estrogen and estrogen related receptor C-terminal domain
| image =
| width =
| caption =
| Pfam= PF12743
| InterPro=
| SMART=
| Prosite =        
| SCOP =
| TCDB =
| OPM family=
| OPM protein=
| PDB=
}}
There are two different forms of the estrogen receptor, usually referred to as '''[[estrogen receptor alpha|α]]''' and '''[[estrogen receptor beta|β]]''', each encoded by a separate gene ({{gene|ESR1}} and {{gene|ESR2}}, respectively). Hormone-activated estrogen receptors form [[protein dimer|dimer]]s, 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.<ref name="pmid15314175">{{cite journal | vauthors = Li X, Huang J, Yi P, Bambara RA, Hilf R, Muyan M | title = Single-chain estrogen receptors (ERs) reveal that the ERalpha/beta heterodimer emulates functions of the ERalpha dimer in genomic estrogen signaling pathways | journal = Molecular and Cellular Biology | volume = 24 | issue = 17 | pages = 7681–7694 | date = September 2004 | pmid = 15314175 | pmc = 506997 | doi = 10.1128/MCB.24.17.7681-7694.2004 }}</ref>
Estrogen receptor alpha and beta show significant overall sequence homology, and both are composed of five [[protein domain|domains]] designated A/B through F (listed from the N- to C-terminus; [[amino acid]] sequence numbers refer to human ER).{{citation needed|date=September 2023}}

The [[N-terminus|N-terminal]] A/B domain is able to [[transactivation|transactivate]] gene transcription in the absence of bound [[ligand (biochemistry)|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 element]]s 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 (genetics)|coactivator]] and [[corepressor (genetics)|corepressor]] proteins. The E-domain in the presence of bound ligand is able to activate gene transcription. The [[C-terminus|C-terminal]] F domain function is not entirely clear and is variable in length.{{citation needed|date=September 2023}}

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.<ref>{{cite journal | vauthors = Nilsson S, Mäkelä S, Treuter E, Tujague M, Thomsen J, Andersson G, Enmark E, Pettersson K, Warner M, Gustafsson JA | title = Mechanisms of estrogen action | journal = Physiological Reviews | volume = 81 | issue = 4 | pages = 1535–1565 | date = October 2001 | pmid = 11581496 | doi = 10.1152/physrev.2001.81.4.1535 | s2cid = 10223568 }}</ref><ref>{{cite journal | vauthors = Leung YK, Mak P, Hassan S, Ho SM | title = Estrogen receptor (ER)-beta isoforms: a key to understanding ER-beta signaling | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 35 | pages = 13162–13167 | date = August 2006 | pmid = 16938840 | pmc = 1552044 | doi = 10.1073/pnas.0605676103 | doi-access = free | bibcode = 2006PNAS..10313162L }}</ref>

Only in fish, but not in humans, an ERγ receptor has been described.<ref>{{cite journal | vauthors = Hawkins MB, Thornton JW, Crews D, Skipper JK, Dotte A, Thomas P | title = Identification of a third distinct estrogen receptor and reclassification of estrogen receptors in teleosts | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 20 | pages = 10751–10756 | date = September 2000 | pmid = 11005855 | pmc = 27095 | doi = 10.1073/pnas.97.20.10751 | doi-access = free | bibcode = 2000PNAS...9710751H }}</ref>

== Tissue distribution ==
Both ERs are widely expressed in different tissue types, however there are some notable differences in their expression patterns:<ref name="pmid9348186">{{cite journal | vauthors = Couse JF, Lindzey J, Grandien K, Gustafsson JA, Korach KS | title = 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 | journal = Endocrinology | volume = 138 | issue = 11 | pages = 4613–4621 | date = November 1997 | pmid = 9348186 | doi = 10.1210/en.138.11.4613 | doi-access = free }}</ref>
* The ''ERα'' is found in [[endometrium]], [[breast cancer]] cells, ovarian stromal cells, and the [[hypothalamus]].<ref name="pmid15990721">{{cite journal | vauthors = Yaghmaie F, Saeed O, Garan SA, Freitag W, Timiras PS, Sternberg H | title = Caloric restriction reduces cell loss and maintains estrogen receptor-alpha immunoreactivity in the pre-optic hypothalamus of female B6D2F1 mice | journal = Neuro Endocrinology Letters | volume = 26 | issue = 3 | pages = 197–203 | date = June 2005 | pmid = 15990721 | url = http://www.nel.edu/pdf_/26_3/260305A01_15990721_Yaghmaie_.pdf }}</ref> In males, ''ERα'' protein is found in the epithelium of the [[efferent ducts]].<ref name="pmid12904263">{{cite journal | vauthors = Hess RA | title = Estrogen in the adult male reproductive tract: a review | journal = Reproductive Biology and Endocrinology | volume = 1 | issue = 52 | pages = 52 | date = July 2003 | pmid = 12904263 | pmc = 179885 | doi = 10.1186/1477-7827-1-52 | doi-access = free }}</ref>
* The expression of the ''ERβ'' protein has been documented in ovarian [[granulosa cells]], [[kidney]], [[brain]], [[bone]], [[heart]],<ref name="pmid11861041">{{cite journal | vauthors = Babiker FA, De Windt LJ, van Eickels M, Grohe C, Meyer R, Doevendans PA | title = Estrogenic hormone action in the heart: regulatory network and function | journal = Cardiovascular Research | volume = 53 | issue = 3 | pages = 709–719 | date = February 2002 | pmid = 11861041 | doi = 10.1016/S0008-6363(01)00526-0 | doi-access = free }}</ref> [[lungs]], [[intestine|intestinal]] mucosa, [[prostate]], and [[endothelium|endothelial]] 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.<ref>{{cite journal | vauthors = Htun H, Holth LT, Walker D, Davie JR, Hager GL | title = Direct visualization of the human estrogen receptor alpha reveals a role for ligand in the nuclear distribution of the receptor | journal = Molecular Biology of the Cell | volume = 10 | issue = 2 | pages = 471–486 | date = February 1999 | pmid = 9950689 | pmc = 25181 | doi = 10.1091/mbc.10.2.471 }}</ref>
The "ERα" primary transcript gives rise to several alternatively spliced variants of unknown function.<ref>{{cite journal | vauthors = Pfeffer U, Fecarotta E, Vidali G | title = Coexpression of multiple estrogen receptor variant messenger RNAs in normal and neoplastic breast tissues and in MCF-7 cells | journal = Cancer Research | volume = 55 | issue = 10 | pages = 2158–2165 | date = May 1995 | pmid = 7743517 }}</ref>

== Signal transduction ==

Since estrogen is a [[steroidal hormone]], it can readily diffuse through the [[phospholipid membrane]]s 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.<ref name="Yaşar_2017">{{cite journal | vauthors = Yaşar P, Ayaz G, User SD, Güpür G, Muyan M | title = Molecular mechanism of estrogen-estrogen receptor signaling | journal = Reproductive Medicine and Biology | volume = 16 | issue = 1 | pages = 4–20 | date = January 2017 | pmid = 29259445 | doi = 10.1002/rmb2.12006 | pmc = 5715874 }}</ref> However, both intracellular and membrane-bound estrogen receptors exist, each mediating different cellular responses to estrogen.<ref name="Fuentes_2019">{{cite journal | vauthors = Fuentes N, Silveyra P | title = Estrogen receptor signaling mechanisms | journal = Advances in Protein Chemistry and Structural Biology | volume = 116 | issue = | pages = 135–170 | date = 2019 | pmid = 31036290 | doi = 10.1016/bs.apcsb.2019.01.001 | pmc = 6533072 }}</ref>

=== Genomic ===
In the absence of hormone, estrogen receptors are predominantly located in the cytoplasm.<ref name = "Dahlman-Wright_2006">{{cite journal | vauthors = Dahlman-Wright K, Cavailles V, Fuqua SA, Jordan VC, Katzenellenbogen JA, Korach KS, Maggi A, Muramatsu M, Parker MG, Gustafsson JA | title = International Union of Pharmacology. LXIV. Estrogen receptors | journal = Pharmacological Reviews | volume = 58 | issue = 4 | pages = 773–781 | date = December 2006 | pmid = 17132854 | doi = 10.1124/pr.58.4.8 | s2cid = 45996586 }}</ref> 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 element]]s, initiating the process of [[gene regulation]].

The DNA/receptor complex then recruits other proteins responsible for [[transcription (genetics)|transcription]] of downstream DNA into mRNA and ultimately protein, resulting in changes in cell function.<ref name = "Dahlman-Wright_2006" /> Estrogen receptors are also present within the [[cell nucleus]], and both estrogen receptor subtypes (ERα and ERβ) contain a [[DNA]]-binding [[protein domain|domain]], allowing them to function as [[transcription factor]]s regulating [[protein]] production.<ref name = "Levin_2005">{{cite journal | vauthors = Levin ER | title = Integration of the extranuclear and nuclear actions of estrogen | journal = Molecular Endocrinology | volume = 19 | issue = 8 | pages = 1951–1959 | date = August 2005 | pmid = 15705661 | pmc = 1249516 | doi = 10.1210/me.2004-0390 }}</ref>

The receptor also interacts with transcription factors such as [[AP-1 (transcription factor)|activator protein 1]] and [[Sp1 (biology)|Sp-1]] to promote transcription, via several coactivators including [[PELP-1]].<ref name = "Dahlman-Wright_2006" /> [[Tumor suppressor gene|Tumor suppressor]] [[kinase]] [[STK11|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.<ref>{{cite journal | vauthors = Nath-Sain S, Marignani PA | title = LKB1 catalytic activity contributes to estrogen receptor alpha signaling | journal = Molecular Biology of the Cell | volume = 20 | issue = 11 | pages = 2785–2795 | date = June 2009 | pmid = 19369417 | pmc = 2688557 | doi = 10.1091/MBC.E08-11-1138 }}</ref> Direct acetylation of estrogen receptor alpha at lysine residues in the hinge region by p300 regulates transactivation and hormone sensitivity.<ref name="Wang_2001">{{cite journal | vauthors = Wang C, Fu M, Angeletti RH, Siconolfi-Baez L, Reutens AT, Albanese C, Lisanti MP, Katzenellenbogen BS, Kato S, Hopp T, Fuqua SA, Lopez GN, Kushner PJ, Pestell RG | title = Direct acetylation of the estrogen receptor alpha hinge region by p300 regulates transactivation and hormone sensitivity | journal = The Journal of Biological Chemistry | volume = 276 | issue = 21 | pages = 18375–83 | date = May 2001 | pmid = 11279135 | doi = 10.1074/jbc.M100800200 | doi-access = free }}</ref>

=== Non-genomic ===
Nuclear estrogen receptors can also associate with the [[plasma membrane|cell surface membrane]] and undergo rapid activation upon cellular exposure to estrogen.<ref name="pmid15642158">{{cite journal | vauthors = Zivadinovic D, Gametchu B, Watson CS | title = Membrane estrogen receptor-alpha levels in MCF-7 breast cancer cells predict cAMP and proliferation responses | journal = Breast Cancer Research | volume = 7 | issue = 1 | pages = R101–R112 | year = 2005 | pmid = 15642158 | pmc = 1064104 | doi = 10.1186/bcr958 | doi-access = free }}</ref><ref name="Björnström_2004">{{cite journal | vauthors = Björnström L, Sjöberg M | title = Estrogen receptor-dependent activation of AP-1 via non-genomic signalling | journal = Nuclear Receptor | volume = 2 | issue = 1 | pages = 3 | date = June 2004 | pmid = 15196329 | pmc = 434532 | doi = 10.1186/1478-1336-2-3 | doi-access = free }}</ref>

Some ERs interact with cell membranes by binding to [[Caveolin|caveolin-1]] and forming complexes with [[G protein]]s, [[STRN|striatin]], receptor [[tyrosine kinase]]s (e.g., [[Epidermal growth factor receptor|EGFR]] and [[IGF-1]]), and non-receptor tyrosine kinases (e.g., [[Src (gene)|Src]]).<ref name=pmid15705661/><ref name=pmid15642158/> Membrane-bound ERs associated with striatin can increase levels of [[calcium|Ca<sup>2+</sup>]] and [[nitric oxide]] (NO).<ref name="pmid15569929">{{cite journal | vauthors = Lu Q, Pallas DC, Surks HK, Baur WE, Mendelsohn ME, Karas RH | title = Striatin assembles a membrane signaling complex necessary for rapid, nongenomic activation of endothelial NO synthase by estrogen receptor alpha | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 49 | pages = 17126–17131 | date = December 2004 | pmid = 15569929 | pmc = 534607 | doi = 10.1073/pnas.0407492101 | doi-access = free | bibcode = 2004PNAS..10117126L }}</ref> 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.<ref name="pmid7491495">{{cite journal | vauthors = Kato S, Endoh H, Masuhiro Y, Kitamoto T, Uchiyama S, Sasaki H, Masushige S, Gotoh Y, Nishida E, Kawashima H, Metzger D, Chambon P | title = Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase | journal = Science | volume = 270 | issue = 5241 | pages = 1491–1494 | date = December 1995 | pmid = 7491495 | doi = 10.1126/science.270.5241.1491 | s2cid = 4662264 | bibcode = 1995Sci...270.1491K }}</ref>

[[GSK-3|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 [[Ribosomal s6 kinase|rsk]].

17β-Estradiol has been shown to activate the [[G protein-coupled receptor]] [[GPR30]].<ref name="pmid17222505">{{cite journal | vauthors = Prossnitz ER, Arterburn JB, Sklar LA | title = GPR30: A G protein-coupled receptor for estrogen | journal = Molecular and Cellular Endocrinology | volume = 265-266 | pages = 138–142 | date = February 2007 | pmid = 17222505 | pmc = 1847610 | doi = 10.1016/j.mce.2006.12.010 }}</ref> However, the subcellular localization and precise role of this receptor remain controversial.<ref name="pmid18566127">{{cite journal | vauthors = Otto C, Rohde-Schulz B, Schwarz G, Fuchs I, Klewer M, Brittain D, Langer G, Bader B, Prelle K, Nubbemeyer R, Fritzemeier KH | title = G protein-coupled receptor 30 localizes to the endoplasmic reticulum and is not activated by estradiol | journal = Endocrinology | volume = 149 | issue = 10 | pages = 4846–4856 | date = October 2008 | pmid = 18566127 | doi = 10.1210/en.2008-0269 | doi-access = free }}</ref>

== Clinical significance ==
[[File:Nolvadex.jpg|thumb|160px|Nolvadex ([[tamoxifen]]) 20 mg]]
[[File:Arimidex.jpg|thumb|160px|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]]. 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 gland|mammary cell]]s, 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 polymorphism]]s) and are associated with different risks of developing breast cancer.<ref name="pmid16511588"/>

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.<ref name="pmid14500559">{{cite journal | vauthors = Harris HA, Albert LM, Leathurby Y, Malamas MS, Mewshaw RE, Miller CP, Kharode YP, Marzolf J, Komm BS, Winneker RC, Frail DE, Henderson RA, Zhu Y, Keith JC | title = Evaluation of an estrogen receptor-beta agonist in animal models of human disease | journal = Endocrinology | volume = 144 | issue = 10 | pages = 4241–4249 | date = October 2003 | pmid = 14500559 | doi = 10.1210/en.2003-0550 | doi-access = free }}</ref>

[[Endocrine]] therapy for breast cancer involves [[selective estrogen receptor modulator]]s (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.<ref name="pmid12363457">{{cite journal | vauthors = Clemons M, Danson S, Howell A | title = Tamoxifen ("Nolvadex"): a review | journal = Cancer Treatment Reviews | volume = 28 | issue = 4 | pages = 165–180 | date = August 2002 | pmid = 12363457 | doi = 10.1016/s0305-7372(02)00036-1 }}</ref>  Another SERM, [[raloxifene]], has been used as a preventive chemotherapy for women judged to have a high risk of developing breast cancer.<ref name="pmid15755972">{{cite journal | vauthors = Fabian CJ, Kimler BF | title = Selective estrogen-receptor modulators for primary prevention of breast cancer | journal = Journal of Clinical Oncology | volume = 23 | issue = 8 | pages = 1644–1655 | date = March 2005 | pmid = 15755972 | doi = 10.1200/JCO.2005.11.005 | doi-access = free }}</ref>    Another chemotherapeutic anti-estrogen, [[ICI 182,780]] (Faslodex), which acts as a complete antagonist, also promotes degradation of the estrogen receptor.

However, ''[[Mutation|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.<ref>{{cite journal | vauthors = Oesterreich S, Davidson NE | title = The search for ESR1 mutations in breast cancer | journal = Nature Genetics | volume = 45 | issue = 12 | pages = 1415–1416 | date = December 2013 | pmid = 24270445 | pmc = 4934882 | doi = 10.1038/ng.2831 }}</ref> 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.<ref>{{cite journal | vauthors = Li S, Shen D, Shao J, Crowder R, Liu W, Prat A, He X, Liu S, Hoog J, Lu C, Ding L, Griffith OL, Miller C, Larson D, Fulton RS, Harrison M, Mooney T, McMichael JF, Luo J, Tao Y, Goncalves R, Schlosberg C, Hiken JF, Saied L, Sanchez C, Giuntoli T, Bumb C, Cooper C, Kitchens RT, Lin A, Phommaly C, Davies SR, Zhang J, Kavuri MS, McEachern D, Dong YY, Ma C, Pluard T, Naughton M, Bose R, Suresh R, McDowell R, Michel L, Aft R, Gillanders W, DeSchryver K, Wilson RK, Wang S, Mills GB, Gonzalez-Angulo A, Edwards JR, Maher C, Perou CM, Mardis ER, Ellis MJ | title = Endocrine-therapy-resistant ESR1 variants revealed by genomic characterization of breast-cancer-derived xenografts | journal = Cell Reports | volume = 4 | issue = 6 | pages = 1116–1130 | date = September 2013 | pmid = 24055055 | pmc = 3881975 | doi = 10.1016/j.celrep.2013.08.022 }}</ref>

=== Menopause ===
The metabolic effects of estrogen in postmenopausal women has been linked to the genetic polymorphism of [[Estrogen receptor beta|estrogen receptor beta (ER-β)]].<ref name="pmid21117950">{{cite journal | vauthors = Darabi M, Ani M, Panjehpour M, Rabbani M, Movahedian A, Zarean E | title = Effect of estrogen receptor β A1730G polymorphism on ABCA1 gene expression response to postmenopausal hormone replacement therapy | journal = Genetic Testing and Molecular Biomarkers | volume = 15 | issue = 1–2 | pages = 11–15 | year = 2011 | pmid = 21117950 | doi = 10.1089/gtmb.2010.0106 }}</ref>

=== 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.<ref name="pmid15990721"/>

=== Obesity ===
A dramatic demonstration of the importance of estrogens in the regulation of fat deposition comes from [[Genetically modified organism|transgenic mice]] that were genetically engineered to lack a functional [[aromatase]] gene. These mice have very low levels of estrogen and are obese.<ref name="pmid12933663">{{cite journal | vauthors = Hewitt KN, Boon WC, Murata Y, Jones ME, Simpson ER | title = The aromatase knockout mouse presents with a sexually dimorphic disruption to cholesterol homeostasis | journal = Endocrinology | volume = 144 | issue = 9 | pages = 3895–3903 | date = September 2003 | pmid = 12933663 | doi = 10.1210/en.2003-0244 | doi-access = free }}</ref> Obesity was also observed in estrogen deficient female mice lacking the [[follicle-stimulating hormone receptor]].<ref name="pmid11089565">{{cite journal | vauthors = Danilovich N, Babu PS, Xing W, Gerdes M, Krishnamurthy H, Sairam MR | title = Estrogen deficiency, obesity, and skeletal abnormalities in follicle-stimulating hormone receptor knockout (FORKO) female mice | journal = Endocrinology | volume = 141 | issue = 11 | pages = 4295–4308 | date = November 2000 | pmid = 11089565 | doi = 10.1210/endo.141.11.7765 | doi-access = free }}</ref> The effect of low estrogen on increased obesity has been linked to estrogen receptor alpha.<ref name="pmid11095962">{{cite journal | vauthors = Ohlsson C, Hellberg N, Parini P, Vidal O, Bohlooly-Y M, Rudling M, Lindberg MK, Warner M, Angelin B, Gustafsson JA | title = Obesity and disturbed lipoprotein profile in estrogen receptor-alpha-deficient male mice | journal = Biochemical and Biophysical Research Communications | volume = 278 | issue = 3 | pages = 640–645 | date = November 2000 | pmid = 11095962 | doi = 10.1006/bbrc.2000.3827 }}</ref>

=== SERMs for other treatment purposes ===
SERMs are also being studied for the treatment of [[uterine fibroid]]s<ref name=":0">{{cite journal | vauthors = Deng L, Wu T, Chen XY, Xie L, Yang J | title = Selective estrogen receptor modulators (SERMs) for uterine leiomyomas | journal = The Cochrane Database of Systematic Reviews | volume = 10 | pages = CD005287 | date = October 2012 | pmid = 23076912 | doi = 10.1002/14651858.CD005287.pub4 }}</ref> and [[endometriosis]].<ref name=":1">{{cite journal | vauthors = van Hoesel MH, Chen YL, Zheng A, Wan Q, Mourad SM | title = Selective oestrogen receptor modulators (SERMs) for endometriosis | journal = The Cochrane Database of Systematic Reviews | volume = 2021 | issue = 5 | pages = CD011169 | date = May 2021 | pmid = 33973648 | pmc = 8130989 | doi = 10.1002/14651858.CD011169.pub2 | collaboration = Cochrane Gynaecology and Fertility Group }}</ref> 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.<ref name=":0" /> It is also not clear if SERMs is effective for treating endometriosis.<ref name=":1" />

=== 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 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 [[Non-Mendelian inheritance|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 [[gonad]]s produce markedly higher levels of [[estrogen]] for individuals with EIS (119–272 pg/mL XY and 750–3,500 pg/mL XX, see [[Estradiol#Levels|average levels]]) however no [[Feminization (biology)|feminizing]] effects occur.<ref>{{cite book| vauthors = Lemke TL, Williams DA |title=Foye's Principles of Medicinal Chemistry|url=https://books.google.com/books?id=Sd6ot9ul-bUC&pg=PA1392|date=24 January 2012|publisher=Lippincott Williams & Wilkins|isbn=978-1-60913-345-0|pages=1392–}}</ref><ref>{{cite journal | vauthors = Smith EP, Boyd J, Frank GR, Takahashi H, Cohen RM, Specker B, Williams TC, Lubahn DB, Korach KS | title = Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man | journal = The New England Journal of Medicine | volume = 331 | issue = 16 | pages = 1056–1061 | date = October 1994 | pmid = 8090165 | doi = 10.1056/NEJM199410203311604 | doi-access = free }}</ref>

==Ligands==

===Agonists===
* [[Endogenous]] [[estrogen]]s (e.g., [[estradiol]], [[estrone]], [[estriol]], [[estetrol]])
* [[Natural product|Natural]] [[estrogen]]s (e.g., [[conjugated estrogens]])
* [[Synthetic compound|Synthetic]] [[estrogen]]s (e.g., [[ethinylestradiol]], [[diethylstilbestrol]])

===Mixed (agonist and antagonist mode of action)===
* [[Phytoestrogen]]s (e.g., [[coumestrol]], [[daidzein]], [[genistein]], [[miroestrol]])
* [[Selective estrogen receptor modulator]]s (e.g., [[tamoxifen]], [[clomifene]], [[raloxifene]])

===Antagonists===
* [[Antiestrogen]]s (e.g., [[fulvestrant]], [[ICI-164384]], [[ethamoxytriphetol]])

===Affinities===
{{Affinities of estrogen receptor ligands for the ERα and ERβ}}

===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.<ref>{{cite journal | vauthors = Ascenzi P, Bocedi A, Marino M | title = Structure-function relationship of estrogen receptor alpha and beta: impact on human health | journal = Molecular Aspects of Medicine | volume = 27 | issue = 4 | pages = 299–402 | date = August 2006 | pmid = 16914190 | doi = 10.1016/j.mam.2006.07.001 }}</ref><ref>{{cite journal | vauthors = Bourguet W, Germain P, Gronemeyer H | title = Nuclear receptor ligand-binding domains: three-dimensional structures, molecular interactions and pharmacological implications | journal = Trends in Pharmacological Sciences | volume = 21 | issue = 10 | pages = 381–388 | date = October 2000 | pmid = 11050318 | doi = 10.1016/S0165-6147(00)01548-0 }}</ref>

Different [[ligand]]s may differ in their affinity for alpha and beta isoforms of the estrogen receptor:
* [[17β-estradiol|estradiol]] binds equally well to both receptors<ref name=pmid16728493>{{cite journal | vauthors = Zhu BT, Han GZ, Shim JY, Wen Y, Jiang XR | title = 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 | journal = Endocrinology | volume = 147 | issue = 9 | pages = 4132–4150 | date = September 2006 | pmid = 16728493 | doi = 10.1210/en.2006-0113 | doi-access =  }}</ref>
* [[estrone]], and [[raloxifene]] bind preferentially to the alpha receptor<ref name=pmid16728493/>
* [[estriol]], and [[genistein]] to the beta receptor<ref name=pmid16728493/>

Subtype [[selective estrogen receptor modulator]]s 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.<ref name="pmid15950373">{{cite journal | vauthors = Kansra S, Yamagata S, Sneade L, Foster L, Ben-Jonathan N | title = Differential effects of estrogen receptor antagonists on pituitary lactotroph proliferation and prolactin release | journal = Molecular and Cellular Endocrinology | volume = 239 | issue = 1–2 | pages = 27–36 | date = July 2005 | pmid = 15950373 | doi = 10.1016/j.mce.2005.04.008 | s2cid = 42052008 }}</ref> The ratio of α- to β- subtype concentration has been proposed to play a role in certain diseases.<ref name="pmid18166184">{{cite journal | vauthors = Bakas P, Liapis A, Vlahopoulos S, Giner M, Logotheti S, Creatsas G, Meligova AK, Alexis MN, Zoumpourlis V | title = Estrogen receptor alpha and beta in uterine fibroids: a basis for altered estrogen responsiveness | journal = Fertility and Sterility | volume = 90 | issue = 5 | pages = 1878–1885 | date = November 2008 | pmid = 18166184 | doi = 10.1016/j.fertnstert.2007.09.019 | hdl-access = free | hdl = 10442/7330 }}</ref>

The concept of selective estrogen receptor modulators is based on the ability to promote ER interactions with different proteins such as [[transcription coregulator|transcriptional]] [[coactivator (genetics)|coactivator]] or [[corepressor (genetics)|corepressor]]s. Furthermore, the ratio of coactivator to corepressor protein varies in different tissues.<ref name="Shang_2002">{{cite journal | vauthors = Shang Y, Brown M | title = Molecular determinants for the tissue specificity of SERMs | journal = Science | volume = 295 | issue = 5564 | pages = 2465–2468 | date = March 2002 | pmid = 11923541 | doi = 10.1126/science.1068537 | s2cid = 30634073 | bibcode = 2002Sci...295.2465S }}</ref>  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<ref name="pmid16511588">{{cite journal | vauthors = Deroo BJ, Korach KS | title = Estrogen receptors and human disease | journal = The Journal of Clinical Investigation | volume = 116 | issue = 3 | pages = 561–570 | date = March 2006 | pmid = 16511588 | pmc = 2373424 | doi = 10.1172/JCI27987 }}</ref> 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,<ref name="pmid12796359">{{cite journal | vauthors = Jensen EV, Jordan VC | title = The estrogen receptor: a model for molecular medicine | journal = Clinical Cancer Research | volume = 9 | issue = 6 | pages = 1980–1989 | date = June 2003 | pmid = 12796359 | url = http://clincancerres.aacrjournals.org/cgi/content/abstract/9/6/1980 | format = abstract }}</ref><ref name="pmid21888507">{{cite journal | vauthors = Jensen E | title = A conversation with Elwood Jensen. Interview by David D. Moore | journal = Annual Review of Physiology | volume = 74 | pages = 1–11 | year = 2011 | pmid = 21888507 | doi = 10.1146/annurev-physiol-020911-153327 | doi-access = free }}</ref> for which Jensen was awarded the [[Lasker Award]].<ref>{{cite web | vauthors = Bracey D | date = 2004 | url = http://www.uc.edu/news/NR.asp?id=1993 | title = UC Scientist Wins 'American Nobel' Research Award | work = University of Cincinnati press release }}</ref> 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.<ref name="pmid8650195">{{cite journal | vauthors = Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA | title = Cloning of a novel receptor expressed in rat prostate and ovary | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 12 | pages = 5925–5930 | date = June 1996 | pmid = 8650195 | pmc = 39164 | doi = 10.1073/pnas.93.12.5925 | doi-access = free }}</ref>

== See also ==
* [[Membrane estrogen receptor]]
* [[Estrogen insensitivity syndrome]]
* [[Aromatase deficiency]]
* [[Aromatase excess syndrome]]

== References ==
{{Reflist|2}}

== External links ==
* {{MeshName|Estrogen Receptors}}
* {{cite web | url = http://www.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb45_1.html | archive-url = https://web.archive.org/web/20060311054007/http://www.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb45_1.html | url-status = dead | archive-date = March 11, 2006 | title = Estrogen Receptor | access-date = 2008-03-15 | vauthors = Goodsell DS | date = September 2003 | publisher = [[Protein Data Bank]], Research Collaboratory for Structural Bioinformatics (RCSB) }}

{{Transcription factors|g2}}
{{Estrogenics}}

{{DEFAULTSORT:Estrogen Receptor}}
[[Category:Human female endocrine system]]
[[Category:Nuclear receptors|3]]