Estrogen receptor alpha

Estrogen receptor alpha (ERα), also known as NR3A1 (nuclear receptor subfamily 3, group A, member 1), is one of two main types of estrogen receptor, a nuclear receptor (mainly found as a chromatin-binding protein^[5]) that is activated by the sex hormone estrogen. In humans, ERα is encoded by the gene ESR1 (EStrogen Receptor 1).^[6][7][8]

ESR1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1A52, 1ERE, 1ERR, 1G50, 1GWQ, 1GWR, 1HCP, 1HCQ, 1L2I, 1PCG, 1QKT, 1QKU, 1R5K, 1SJ0, 1UOM, 1X7E, 1X7R, 1XP1, 1XP6, 1XP9, 1XPC, 1XQC, 1YIM, 1YIN, 1ZKY, 2AYR, 2B1V, 2B1Z, 2B23, 2BJ4, 2FAI, 2G44, 2G5O, 2I0J, 2IOG, 2IOK, 2JF9, 2JFA, 2LLO, 2LLQ, 2OCF, 2OUZ, 2P15, 2POG, 2Q6J, 2Q70, 2QA6, 2QA8, 2QAB, 2QE4, 2QGT, 2QGW, 2QH6, 2QR9, 2QSE, 2QXM, 2QXS, 2QZO, 2R6W, 2R6Y, 2YAT, 2YJA, 3CBM, 3CBO, 3CBP, 3DT3, 3ERD, 3ERT, 3HLV, 3HM1, 3L03, 3OS8, 3OS9, 3OSA, 3Q95, 3Q97, 3UU7, 3UUA, 3UUC, 3UUD, 4AA6, 4DMA, 4IU7, 4IUI, 4IV2, 4IV4, 4IVW, 4IVY, 4IW6, 4IW8, 4IWC, 4IWF, 4JC3, 4JDD, 4MG5, 4MG6, 4MG7, 4MG8, 4MG9, 4MGA, 4MGB, 4MGC, 4MGD, 4O6F, 4PP6, 4PPP, 4PPS, 4PXM, 4Q13, 4Q50, 4TUZ, 4TV1, 5AK2, 5AAV, 5ACC, 5AAU, 4XI3, 4ZN9, 5FQS, 5FQR, 5FQP, 5FQT, 5FQV, 4ZN7, 5E0W, 5DUG, 4ZUC, 5DXK, 5E19, 5DXQ, 5EI1, 5DXR, 5DVS, 5DZ1, 5E0X, 5DKB, 5DWI, 5E14, 5DXB, 5BPR, 5EIT, 5E15, 4ZNS, 5EGV, 5DL4, 5DWE, 4ZNT, 5EHJ, 5DYD, 5DWG, 4ZNV, 5DWJ, 5DID, 4ZUB, 5BNU, 5DMC, 5DK9, 5DIG, 5DUH, 5DKS, 5DMF, 5DU5, 5DY8, 4ZWH, 5DVV, 5DLR, 4ZWK, 5DRM, 5DP0, 5DKE, 5DZI, 5DZ3, 4ZNU, 5DIE, 5DZ0, 5E1C, 5HYR, 5BQ4, 4ZNW, 5DUE, 5DTV, 5DRJ, 5DKG, 4ZNH, 5BP6, 5DXG, 5DI7, 5DX3, 5DYB, 5DXP, 5DZH, 5DXM
Identifiers
Aliases	ESR1, ER, ESR, ESRA, ESTRR, Era, NR3A1, estrogen receptor 1
External IDs	OMIM: 133430 MGI: 1352467 HomoloGene: 47906 GeneCards: ESR1
Gene location (Human) Chr. Chromosome 6 (human)^[1] Band 6q25.1-q25.2 Start 151,656,691 bp^[1] End 152,129,619 bp^[1]
Gene location (Mouse) Chr. Chromosome 10 (mouse)^[2] Band 10 A1|10 2.03 cM Start 4,561,593 bp^[2] End 4,955,614 bp^[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in cervix epithelium vulva endometrium canal of the cervix right uterine tube lactiferous duct vagina caput epididymis germinal epithelium Achilles tendon Top expressed in vas deferens uterus intercostal muscle triceps brachii muscle sternocleidomastoid muscle temporal muscle ankle left lobe of liver secondary oocyte digastric muscle More reference expression data BioGPS n/a
Gene ontology Molecular function DNA-binding transcription factor activity DNA-binding transcription activator activity, RNA polymerase II-specific nitric-oxide synthase regulator activity nuclear receptor activity estrogen response element binding transcription factor binding metal ion binding RNA polymerase II cis-regulatory region sequence-specific DNA binding steroid hormone receptor activity steroid binding beta-catenin binding zinc ion binding chromatin binding protein binding DNA binding sequence-specific DNA binding ATPase binding identical protein binding lipid binding core promoter sequence-specific DNA binding enzyme binding protein kinase binding TFIIB-class transcription factor binding TBP-class protein binding estrogen receptor activity estrogen receptor binding transcription coactivator binding phosphatidylinositol-4,5-bisphosphate 3-kinase activity DNA-binding transcription factor activity, RNA polymerase II-specific Cellular component cytoplasm membrane nucleus integral component of membrane Golgi apparatus plasma membrane nucleoplasm transcription preinitiation complex cytosol protein-containing complex Biological process epithelial cell development positive regulation of phospholipase C activity mammary gland alveolus development transcription by RNA polymerase II phospholipase C-activating G protein-coupled receptor signaling pathway epithelial cell proliferation involved in mammary gland duct elongation prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis protein localization to chromatin steroid hormone mediated signaling pathway regulation of apoptotic process chromatin remodeling regulation of transcription, DNA-templated androgen metabolic process positive regulation of fibroblast proliferation mammary gland branching involved in pregnancy negative regulation of gene expression transcription, DNA-templated negative regulation of DNA-binding transcription factor activity cellular response to estrogen stimulus positive regulation of transcription, DNA-templated positive regulation of nitric-oxide synthase activity transcription initiation from RNA polymerase II promoter regulation of branching involved in prostate gland morphogenesis male gonad development positive regulation of DNA-binding transcription factor activity negative regulation of transcription by RNA polymerase II negative regulation of I-kappaB kinase/NF-kappaB signaling negative regulation of production of miRNAs involved in gene silencing by miRNA response to estrogen uterus development prostate epithelial cord elongation antral ovarian follicle growth vagina development positive regulation of cytosolic calcium ion concentration positive regulation of nitric oxide biosynthetic process signal transduction positive regulation of transcription by RNA polymerase II intracellular steroid hormone receptor signaling pathway regulation of inflammatory response response to estradiol regulation of toll-like receptor signaling pathway regulation of transcription by RNA polymerase II protein deubiquitination cellular response to estradiol stimulus intracellular estrogen receptor signaling pathway positive regulation of RNA polymerase II transcription preinitiation complex assembly stem cell differentiation regulation of Wnt signaling pathway regulation of intracellular estrogen receptor signaling pathway phosphatidylinositol phosphate biosynthetic process positive regulation of protein kinase B signaling Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 2099 13982 Ensembl ENSG00000091831 ENSMUSG00000019768 UniProt P03372 P19785 RefSeq (mRNA) NM_000125 NM_001122740 NM_001122741 NM_001122742 NM_001291230 NM_001291241 NM_001328100 NM_001385568 NM_001385569 NM_001385570 NM_001385571 NM_001385572 NM_007956 NM_001302531 NM_001302532 NM_001302533 RefSeq (protein) NP_000116 NP_001116212 NP_001116213 NP_001116214 NP_001278159 NP_001278170 NP_001315029 NP_001289460 NP_001289461 NP_001289462 NP_031982 Location (UCSC) Chr 6: 151.66 – 152.13 Mb Chr 10: 4.56 – 4.96 Mb PubMed search ^[3] ^[4]
Wikidata
View/Edit Human View/Edit Mouse

Structure

The estrogen receptor (ER) is a ligand-activated transcription factor composed of several domains important for hormone binding, DNA binding, and activation of transcription.^[9] Alternative splicing results in several ESR1 mRNA transcripts, which differ primarily in their 5-prime untranslated regions. The translated receptors show less variability.^[10][11]

Ligands

Agonists

Non-selective

• Endogenous estrogens (e.g., estradiol, estrone, estriol, estetrol)
• Natural estrogens (e.g., conjugated equine estrogens)
• Synthetic estrogens (e.g., ethinylestradiol, diethylstilbestrol)

Selective

Agonists of ERα selective over ERβ include:

• Propylpyrazoletriol (PPT)
• 16α-LE₂ (Cpd1471)
• 16α-IE₂
• ERA-63 (ORG-37663)
• SKF-82,958 – also a D₁-like receptor full agonist
• (R,R)-Tetrahydrochrysene ((R,R)-THC) – actually not selective over ERβ, but rather an antagonist instead of an agonist of ERβ

Mixed

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

Antagonists

Non-selective

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

Selective

Antagonists of ERα selective over ERβ include:

• Methylpiperidinopyrazole (MPP)

Affinities

• v
• t
• 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	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
Δ^8-Estradiol	8,9-Dehydro-17β-estradiol	68	72	0.15	0.25	Estrogen
Δ^8-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
Δ^4-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.

Tissue distribution and function

ERα plays a role in the physiological development and function of a variety of organ systems to varying degrees, including the reproductive, central nervous, skeletal, and cardiovascular systems.^[12] Accordingly, ERα is widely expressed throughout the body, including the uterus and ovary, male reproductive organs, mammary gland, bone, heart, hypothalamus, pituitary gland, liver, lung, kidney, spleen, and adipose tissue.^[12][13][14] The development and function of these tissues is disrupted in animal models lacking active ERα genes, such as the ERα knockout mouse (ERKO), providing a preliminary understanding of ERα function at specific target organs.^[12][15]

Uterus and ovary

ERα is essential in the maturation of the female reproductive phenotype. In the absence of ERα, the ERKO mouse develops an adult uterus, indicating that ERα may not mediate the initial growth of the uterus.^[12][13] However, ERα plays a role in the completion of this development, and the subsequent function of the tissue.^[15] Activation of ERα is known to trigger cell proliferation in the uterus.^[14] The uterus of female ERKO mice is hypoplastic, suggesting that ERα mediates mitosis and differentiation in the uterus in response to estrogen stimulation.^[13]

Similarly, prepubertal female ERKO mice develop ovaries that are nearly indistinguishable from those of their wildtype counterparts. However, as the ERKO mice mature they progressively present an abnormal ovarian phenotype in both physiology and function.^[13][15] Specifically, female ERKO mice develop enlarged ovaries containing hemorrhagic follicular cysts, which also lack the corpus luteum, and therefore do not ovulate.^[12][13][15] This adult ovarian phenotype suggests that in the absence of ERα, estrogen is no longer able to perform negative feedback on the hypothalamus, resulting in chronically elevated LH levels and constant ovarian stimulation.^[13] These results identify a pivotal role for ERα in the hypothalamus, in addition to its role in the estrogen-driven maturation through theca and interstitial cells of the ovary.^[13]

Male reproductive organs

ERα is similarly essential in the maturation and maintenance of the male reproductive phenotype, as male ERKO mice are infertile and present undersized testes.^[12][15] The integrity of testicular structures of ERKO mice, such as the seminiferous tubules of the testes and the seminiferous epithelium, declines over time.^[12][13] Furthermore, the reproductive performance of male ERKO mice is hindered by abnormalities in sexual physiology and behavior, such as impaired spermatogenesis and loss of intromission and ejaculatory responses.^[12][13]

Mammary gland

Estrogen stimulation of ERα is known to stimulate cell proliferation in breast tissue.^[14] ERα is thought to be responsible for pubertal development of the adult phenotype, through mediation of mammary gland response to estrogens.^[15] This role is consistent with the abnormalities of female ERKO mice: the epithelial ducts of female ERKO mice fail to grow beyond their pre-pubertal length, and lactational structures do not develop.^[13] As a result, the functions of the mammary gland—including both lactation and release of prolactin—are greatly impaired in ERKO mice.^[15]

Bone

Though its expression in bone is moderate, ERα is known to be responsible for maintenance of bone integrity.^[14][15] It is hypothesized that estrogen stimulation of ERα may trigger the release of growth factors, such as epidermal growth factor or insulin-like growth factor-1, which in turn regulate bone development and maintenance.^[15][13] Accordingly, male and female ERKO mice exhibit decreased bone length and size.^[15][13]

Brain

Estrogen signaling through ERα appears to be responsible for various aspects of central nervous development, such as synaptogenesis and synaptic remodeling.^[15] In the brain, ERα is found in hypothalamus, and preoptic area, and arcuate nucleus, all three of which have been linked to reproductive behavior, and the masculinization of the mouse brain appears to take place through ERα function.^[12][15] Furthermore, studies in models of psychopathology and neurodegenerative disease states suggest that estrogen receptors mediate the neuroprotective role of estrogen in the brain.^[12][14] Finally, ERα appears to mediate positive feedback effects of estrogen on the brain's secretion of GnRH and LH, by way increasing expression of kisspeptin in neurons of the arcuate nucleus and anteroventral periventricular nucleus.^[16][17] Although classical studies have suggested that negative feedback effects of estrogen also operate through ERα, female mice lacking ERα in kisspeptin-expressing neurons continue to demonstrate a degree of negative feedback response.^[18]

Clinical significance

Estrogen insensitivity syndrome is a very rare condition characterized by a defective ERα that is insensitive to estrogens.^{[19][20][21][22]} The clinical presentation of a female was observed to include absence of breast development and other female secondary sexual characteristics at puberty, hypoplastic uterus, primary amenorrhea, enlarged multicystic ovaries and associated lower abdominal pain, mild hyperandrogenism (manifested as cystic acne), and delayed bone maturation as well as an increased rate of bone turnover.^[22] The clinical presentation in a male was reported to include lack of epiphyseal closure, tall stature, osteoporosis, and poor sperm viability.^[21] Both individuals were completely insensitive to exogenous estrogen treatment, even with high doses.^[21][22]

Genetic polymorphisms in the gene encoding the ERα have been associated with breast cancer in women, gynecomastia in men^[23][24] and dysmenorrhea.^[25]

In patients with breast cancer, mutations in the gene encoding ERα (ESR1) have been associated with resistance to endocrine therapy, especially aromatase inhibitors.^[26]

Coactivators

Coactivators of ER-α include:

• SRC-1^[27][28]
• AIB1 – amplified in breast 1^[29]
• BCAS3 – Breast carcinoma amplified sequence 3^[30]
• PELP-1 – Proline-, glutamic acid-, leucine-rich protein 1^[31]

Interactions

Estrogen receptor alpha has been shown to interact with:

• AKAP13^[32]
• AHR^[33][34]
• BRCA1^{[35][36][37][38]}
• CAV1^[39]
• CCNC^[40]
• CDC25B^[41]
• CEBPB^[42][43]
• COBRA1^[44]
• COUP-TFI^[45]
• CREBBP^[38][46]
• CRSP3^[40]
• Cyclin D1^[47]
• DDX17^[48]
• DDX5^[48][49]
• DNTTIP2^[50]
• EP300^[38][40][51]
• ESR2^[52][53]
• FOXO1^[54]
• GREB1^[55]
• GTF2H1^[56]
• HSPA1A^[57]
• HSPA8^[57]
• HSP90AA1^[58][59]
• ISL1^[60]
• JARID1A^[61]
• MVP^[62]
• MED1^[40][63]
• MED12^[40]
• MED14^[40]
• MED16^[40]
• MED24^[40][63]
• MED6^[40]
• MGMT^[64]
• MNAT1^[65]
• MTA1^[66][67]
• NCOA6^[68][69]
• NCOA1^{[40][46][48][70][71]}
• NCOA2^{[48][63][72][73][74]}
• NCOA3^[48][75][76]
• NRIP1^[77][78][79]
• PDLIM1^[80]
• POU4F1^[81]
• POU4F2^[81]
• PRDM2^[82]
• PRMT2^[83]
• RBM39^[84]
• RNF12^[80]
• SAFB^[85][86]
• SAFB2^[87]
• SHC1^[88]
• SHP^[89][90]
• SMARCA4^[70][91]
• SMARCE1^[92]
• SRA1^[48]
• Src^{[64][93][94][95]}
• TR2^[96]
• TR4^[97]
• TDG^[98]
• TRIM24^[78][99] and
• XBP1.^[100]

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Further reading

• McDonnell DP, Norris JD (May 2002). "Connections and regulation of the human estrogen receptor". Science. 296 (5573): 1642–1644. Bibcode:2002Sci...296.1642M. doi:10.1126/science.1071884. PMID 12040178. S2CID 30428909.
• Simoncini T, Fornari L, Mannella P, Varone G, Caruso A, Liao JK, Genazzani AR (November 2002). "Novel non-transcriptional mechanisms for estrogen receptor signaling in the cardiovascular system. Interaction of estrogen receptor alpha with phosphatidylinositol 3-OH kinase". Steroids. 67 (12): 935–939. doi:10.1016/S0039-128X(02)00040-5. PMID 12398989. S2CID 42656927.
• Lannigan DA (January 2003). "Estrogen receptor phosphorylation". Steroids. 68 (1): 1–9. doi:10.1016/S0039-128X(02)00110-1. PMID 12475718. S2CID 23163361.
• Herrington DM (April 2003). "Role of estrogen receptor-alpha in pharmacogenetics of estrogen action". Current Opinion in Lipidology. 14 (2): 145–150. doi:10.1097/00041433-200304000-00005. PMID 12642782. S2CID 74820004.
• Tanaka Y, Sasaki M, Kaneuchi M, Fujimoto S, Dahiya R (April 2003). "Estrogen receptor alpha polymorphisms and renal cell carcinoma--a possible risk". Molecular and Cellular Endocrinology. 202 (1–2): 109–116. doi:10.1016/S0303-7207(03)00071-6. PMID 12770739. S2CID 34059244.
• Ali S, Coombes RC (July 2000). "Estrogen receptor alpha in human breast cancer: occurrence and significance". Journal of Mammary Gland Biology and Neoplasia. 5 (3): 271–281. doi:10.1023/A:1009594727358. PMID 14973389. S2CID 23500213.
• Olsson H (July 2000). "Estrogen receptor content in malignant breast tumors in men--a review". Journal of Mammary Gland Biology and Neoplasia. 5 (3): 283–287. doi:10.1023/A:1009546811429. PMID 14973390. S2CID 7342455.
• Surmacz E, Bartucci M (September 2004). "Role of estrogen receptor alpha in modulating IGF-I receptor signaling and function in breast cancer". Journal of Experimental & Clinical Cancer Research. 23 (3): 385–394. PMID 15595626.
• Evinger AJ, Levin ER (2005). "Requirements for estrogen receptor alpha membrane localization and function". Steroids. 70 (5–7): 361–363. doi:10.1016/j.steroids.2005.02.015. PMID 15862818. S2CID 54297122.
• Wang CL, Tang XY, Chen WQ, Su YX, Zhang CX, Chen YM (March 2007). "Association of estrogen receptor alpha gene polymorphisms with bone mineral density in Chinese women: a meta-analysis". Osteoporosis International. 18 (3): 295–305. doi:10.1007/s00198-006-0239-2. PMID 17089081. S2CID 11168531.
• Keaveney M, Klug J, Gannon F (1992). "Sequence analysis of the 5' flanking region of the human estrogen receptor gene". DNA Sequence. 2 (6): 347–358. doi:10.3109/10425179209020816. PMID 1476547.
• Piva R, Gambari R, Zorzato F, Kumar L, del Senno L (March 1992). "Analysis of upstream sequences of the human estrogen receptor gene". Biochemical and Biophysical Research Communications. 183 (3): 996–1002. doi:10.1016/S0006-291X(05)80289-X. PMID 1567414.
• Reese JC, Katzenellenbogen BS (May 1992). "Characterization of a temperature-sensitive mutation in the hormone binding domain of the human estrogen receptor. Studies in cell extracts and intact cells and their implications for hormone-dependent transcriptional activation". The Journal of Biological Chemistry. 267 (14): 9868–9873. doi:10.1016/S0021-9258(19)50174-0. PMID 1577818.
• Dotzlaw H, Alkhalaf M, Murphy LC (May 1992). "Characterization of estrogen receptor variant mRNAs from human breast cancers". Molecular Endocrinology. 6 (5): 773–785. doi:10.1210/mend.6.5.1603086. PMID 1603086. S2CID 25208340.
• Keaveney M, Klug J, Dawson MT, Nestor PV, Neilan JG, Forde RC, Gannon F (February 1991). "Evidence for a previously unidentified upstream exon in the human oestrogen receptor gene". Journal of Molecular Endocrinology. 6 (1): 111–115. doi:10.1677/jme.0.0060111. PMID 2015052.
• Reese JC, Katzenellenbogen BS (June 1991). "Mutagenesis of cysteines in the hormone binding domain of the human estrogen receptor. Alterations in binding and transcriptional activation by covalently and reversibly attaching ligands". The Journal of Biological Chemistry. 266 (17): 10880–10887. doi:10.1016/S0021-9258(18)99101-5. PMID 2040605.
• Schwabe JW, Neuhaus D, Rhodes D (November 1990). "Solution structure of the DNA-binding domain of the oestrogen receptor". Nature. 348 (6300): 458–461. Bibcode:1990Natur.348..458S. doi:10.1038/348458a0. PMID 2247153. S2CID 4349385.
• Tora L, Mullick A, Metzger D, Ponglikitmongkol M, Park I, Chambon P (July 1989). "The cloned human oestrogen receptor contains a mutation which alters its hormone binding properties". The EMBO Journal. 8 (7): 1981–1986. doi:10.1002/j.1460-2075.1989.tb03604.x. PMC 401066. PMID 2792078.
• Ponglikitmongkol M, Green S, Chambon P (November 1988). "Genomic organization of the human oestrogen receptor gene". The EMBO Journal. 7 (11): 3385–3388. doi:10.1002/j.1460-2075.1988.tb03211.x. PMC 454836. PMID 3145193.
• Greene GL, Gilna P, Waterfield M, Baker A, Hort Y, Shine J (March 1986). "Sequence and expression of human estrogen receptor complementary DNA". Science. 231 (4742): 1150–1154. Bibcode:1986Sci...231.1150G. doi:10.1126/science.3753802. PMID 3753802.

External links

• FactorBook ERalpha_a
• Overview of all the structural information available in the PDB for UniProt: P03372 (Estrogen receptor) at the PDBe-KB.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.