ESR2 (Estrogen Receptor 2 (ER beta))

2008-04-01   Chunyan Zhao , Karin Dahlman-Wright , Jan-Ake Gustafsson 

Department of Biosciences, Nutrition, Novum, Karolinska Institutet, S-141 57 Huddinge, Sweden

Identity

HGNC
LOCATION
14q23.2
LOCUSID
ALIAS
ER-BETA,ESR-BETA,ESRB,ESTRB,Erb,NR3A2,ODG8

DNA/RNA

Atlas Image
Genomic organization of human ER beta gene, protein and functional domains.
Gene: exons are indicated with boxes and introns with lines. The numbers above each box indicate the size of the exons (bp); the numbers below each line designate the size of the respective introns (bp). Dotted lines between gene and protein point to protein domain junctions.
Protein: numbers indicate the total size of the protein in amino acids. The shaded bar shows the divergent C-terminal regions between the isoforms.

Description

ER beta gene consists of 8 encoding exons. The open reading frame of the coding region is 1,593 bp.

Proteins

Expression

ER beta is mainly expressed in tissues such as the ovary (granulosa cells), prostate (epithelium), testis, epididymis, colon, lung, bladder, bone marrow, salivary gland, vascular endothelium and regions of the brain, including hypothalamus and cortex.

Localisation

Nucleus

Function

Cellular signaling of estrogen is mediated through two estrogen receptors (ERs), ER alpha and ER beta. The first ER, now known as ER alpha, was cloned in 1986. This receptor was regarded as the only ER that mediates estrogenic effects, until a second ER, now known as ER beta, was cloned from rat prostate. ER alpha and ER beta belong to the superfamily of nuclear receptors and specifically to the family of steroid receptors that act as ligand-regulated transcription factors. ER alpha and ER beta have a high sequence homology and share affinity for the same ligands and DNA response elements.
Binding of ligand activates ERs, by a mechanism that involves dissociation of heat shock proteins and dimerization of receptor proteins. Estrogen-modulated gene transcription is exerted via different mechanisms: the genomic and the nongenomic pathways. The canonical model for ER-mediated regulation of gene expression involves the direct binding of dimeric ER to DNA sequences known as estrogen response elements (EREs), followed by recruitment of a variety of coregulators to alter chromatin structure and facilitate recruitment of the RNA polymerase II (Pol II) transcriptional machinery.
The transcriptional activity of ERs can be modulated by different types of post-translational modifications such as phosphorylation, acetylation, sumoylation, ubiquitination and methylation.
ER alpha and ER beta exhibit different affinities for some natural compounds, and distinct expression patterns in a variety of tissues. Transcriptional activation by ER alpha is mediated by two distinct activation functions: the constitutively active AF-1 and the ligand-dependent AF-2. ER beta seems to have a weaker corresponding AF-1 function and thus depends more on the AF-2 for its transcriptional activation function. ER alpha and ER beta have different activities in certain ligand, cell-type, and promoter contexts.

Homology

Chimpanzee (Pan troglodytes), dog (Canis lupus familiaris), cow (Bos taurus), mouse (Mus musculus), rat (Rattus norvegicus) chicken (Gallus gallus), zebrafish (Danio rerio).

Implicated in

Entity name
Various cancers
Note
Targeted disruption of ER beta in mice has suggested roles for ER beta in many tissues and organs, including the ovary, uterus, mammary gland, brain, immune system and ventral prostate.
Entity name
Prostate cancer
Disease
Estrogens can have profound effects on prostate growth and differentiation as well as in the pathogenesis of prostate cancer. In the adult rodent ventral prostate, ER beta is expressed in the epithelial cells, whereas ER alpha is expressed in the stroma. The estrogenic effects in the prostate may therefore be exerted by both ERs but in different cells. ER beta knockout mice display signs of prostatic hyperplasia with aging.
Entity name
Breast cancer
Disease
Estrogen is essential for growth and development of the mammary glands, and has been associated with promotion and growth of breast cancer. ER beta is found in both ductal and lobular epithelial and stromal cells of the rodent, whereas ER alpha is only found in the ductal and lobular epithelial cells and not in stroma. Recent studies have indicated a protective role of ER beta against breast cancer development. In vitro studies indicated that ER beta is an important modulator of proliferation and invasion of breast cancer cells.
Entity name
Colon cancer
Disease
ER beta is the predominant ER in the colonic epithelium, suggesting that effects of estrogen in the colon are mediated by ER beta. In colons from ER beta knockout mice, the number of proliferating cells was higher, and the migration of labelled cells from base to lumen of the crypts was faster when compared to wild-type mice. Additionally, immunohistochemical staining revealed fewer apoptotic cells (cleaved caspase 3-positive), a significant decrease in expression of the epithelial differentiation marker, cytokeratin CK20, the adherens junction protein, alpha -catenin, and the hemidesmosomal protein, plectin, in ER beta knockout mice. These findings suggest a role for ER beta in the organization and architectural maintenance of the colon.
Entity name
Ovarian cancer
Disease
A loss of ER beta expression or a decrease in ER beta/ER alpha ratio in epithelial ovarian cancer cells as compared with normal tissues has been reported by several groups. ER beta overexpression in ovarian cancer cells has been reported to exert antitumoral effects.

Bibliography

Pubmed IDLast YearTitleAuthors
171328542006International Union of Pharmacology. LXIV. Estrogen receptors.Dahlman-Wright K et al
165567372007Estrogen receptor-beta: recent lessons from in vivo studies.Harris HA et al
86501951996Cloning of a novel receptor expressed in rat prostate and ovary.Kuiper GG et al
115814962001Mechanisms of estrogen action.Nilsson S et al
96718111998Molecular cloning and characterization of human estrogen receptor betacx: a potential inhibitor ofestrogen action in human.Ogawa S et al
183017832008Estrogen receptor beta: an overview and update.Zhao C et al

Other Information

Locus ID:

NCBI: 2100
MIM: 601663
HGNC: 3468
Ensembl: ENSG00000140009

Variants:

dbSNP: 2100
ClinVar: 2100
TCGA: ENSG00000140009
COSMIC: ESR2

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000140009ENST00000267525Q92731
ENSG00000140009ENST00000341099Q92731
ENSG00000140009ENST00000341099Q7LCB3
ENSG00000140009ENST00000344288Q92731
ENSG00000140009ENST00000353772Q92731
ENSG00000140009ENST00000353772F1D8N3
ENSG00000140009ENST00000358599Q92731
ENSG00000140009ENST00000358599F1D8N3
ENSG00000140009ENST00000553796Q92731
ENSG00000140009ENST00000553796A0A348FV93
ENSG00000140009ENST00000554572Q92731
ENSG00000140009ENST00000554572F1D8N3
ENSG00000140009ENST00000555278Q92731
ENSG00000140009ENST00000556275G3V5S2
ENSG00000140009ENST00000557772Q92731

Expression (GTEx)

0
1
2
3
4
5

Pathways

PathwaySourceExternal ID
Estrogen signaling pathwayKEGGhsa04915
Estrogen signaling pathwayKEGGko04915
Prolactin signaling pathwayKEGGhsa04917
Prolactin signaling pathwayKEGGko04917
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Nuclear Receptor transcription pathwayREACTOMER-HSA-383280
Endocrine resistanceKEGGko01522
Endocrine resistanceKEGGhsa01522
Breast cancerKEGGko05224
Breast cancerKEGGhsa05224

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA152241907lapatinibChemicalLabelAnnotationassociated
PA164746311everolimusChemicalLabelAnnotationassociated
PA164747170fulvestrantChemicalLabelAnnotationassociated
PA164747674goserelinChemicalLabelAnnotationassociated
PA164920420olaparibChemicalLabelAnnotationassociated
PA165110439ixabepiloneChemicalLabelAnnotationassociated
PA165290933pertuzumabChemicalLabelAnnotationassociated
PA165291472neratinibChemicalLabelAnnotationassociated
PA166153469palbociclibChemicalLabelAnnotationassociated
PA166153470ribociclibChemicalLabelAnnotationassociated
PA166153471abemaciclibChemicalLabelAnnotationassociated
PA166182723eribulinChemicalLabelAnnotationassociated
PA166184523alpelisibChemicalLabelAnnotationassociated
PA443560Breast NeoplasmsDiseaseClinicalAnnotationassociatedPD26536870
PA445218Pancreatic NeoplasmsDiseaseClinicalAnnotationassociatedPD22838950
PA448432anastrozoleChemicalLabelAnnotationassociated
PA449383docetaxelChemicalLabelAnnotationassociated
PA449563exemestaneChemicalLabelAnnotationassociated
PA449748gemcitabineChemicalClinicalAnnotationassociatedPD22838950
PA450196letrozoleChemicalClinicalAnnotation, LabelAnnotationassociatedPD26536870
PA451221raloxifeneChemicalLabelAnnotationassociated
PA451581tamoxifenChemicalClinicalAnnotation, LabelAnnotationassociatedPD17713466
PA451731toremifeneChemicalLabelAnnotationassociated
PA451743trastuzumabChemicalLabelAnnotationassociated

References

Pubmed IDYearTitleCitations
147296542004Estrogen receptor beta inhibits human breast cancer cell proliferation and tumor formation by causing a G2 cell cycle arrest.178
166450382006Nature of functional estrogen receptors at the plasma membrane.177
182162192008Crosstalk between the estrogen receptor and the HER tyrosine kinase receptor family: molecular mechanism and clinical implications for endocrine therapy resistance.173
147450182004Estrogen receptor beta inhibits 17beta-estradiol-stimulated proliferation of the breast cancer cell line T47D.153
127741242003Modulation of oestrogen receptor signalling by association with the activated dioxin receptor.142
168094422006Impact of estrogen receptor beta on gene networks regulated by estrogen receptor alpha in breast cancer cells.136
169388402006Estrogen receptor (ER)-beta isoforms: a key to understanding ER-beta signaling.123
215656152011An ADIOL-ERβ-CtBP transrepression pathway negatively regulates microglia-mediated inflammation.110
119863162002Opposing action of estrogen receptors alpha and beta on cyclin D1 gene expression.99
195982352009Genes related to sex steroids, neural growth, and social-emotional behavior are associated with autistic traits, empathy, and Asperger syndrome.92

Citation

Chunyan Zhao ; Karin Dahlman-Wright ; Jan-Ake Gustafsson

ESR2 (Estrogen Receptor 2 (ER beta))

Atlas Genet Cytogenet Oncol Haematol. 2008-04-01

Online version: http://atlasgeneticsoncology.org/gene/40500/esr2