Estrogen receptor

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estrogen receptor 1 (ER-alpha)
PBB Protein ESR1 image.png
A dimer of the ligand-binding region of ERα (PDB rendering based on 3erd).
Identifiers
Symbol ESR1
Alt. symbols ER-α, NR3A1
Entrez 2099
HUGO 3467
OMIM 133430
PDB 1ERE (RCSB PDB PDBe PDBj)
RefSeq NM_000125
UniProt P03372
Other data
Locus Chr. 6 q24-q27
estrogen receptor 2 (ER-beta)
Estrogen receptor beta 1U3S.png
A dimer of the ligand-binding region of ERβ (PDB rendering based on 1u3s).
Identifiers
Symbol ESR2
Alt. symbols ER-β, NR3A2
Entrez 2100
HUGO 3468
OMIM 601663
PDB 1QKM (RCSB PDB PDBe PDBj)
RefSeq NM_001040275
UniProt Q92731
Other data
Locus Chr. 14 q21-q22

Estrogen receptors are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen (17β-estradiol).[1] Two classes of estrogen receptor exist: ER, which is a member of the nuclear hormone family of intracellular receptors, and GPR30, which is a member of the rhodopsin-like family of G protein-coupled receptors. This article refers to the former (ER).

Once activated by estrogen, the ER is able to translocate into the nucleus and bind to DNA to regulate the activity of different genes (i.e. it is a DNA-binding transcription factor). However, it also has additional functions independent of DNA binding.[2]

Proteomics[edit]

There are two different forms of the estrogen receptor, usually referred to as α and β, each encoded by a separate gene (ESR1 and ESR2, respectively). Hormone-activated estrogen receptors form dimers, and, since the two forms are coexpressed in many cell types, the receptors may form ERα (αα) or ERβ (ββ) homodimers or ERαβ (αβ) heterodimers.[3] Estrogen receptor alpha and beta show significant overall sequence homology, and both are composed of five domains (listed from the N- to C-terminus; amino acid sequence numbers refer to human ER):(A-F domain)

The domain structures of ERα and ERβ, including some of the known phosphorylation sites involved in ligand-independent regulation.

The N-terminal A/B domain is able to transactivate gene transcription in the absence of bound 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 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 for coactivator and corepressor proteins. The E-domain in the presence of bound ligand is able to activate gene transcription. The C-terminal F domain function is not entirely clear and is variable in length.

Estrogen receptor alpha
N-terminal AF1 domain
Identifiers
Symbol Oest_recep
Pfam PF02159
InterPro IPR001292
SCOP 1hcp
SUPERFAMILY 1hcp
Estrogen and estrogen related receptor C-terminal domain
Identifiers
Symbol ESR1_C
Pfam PF12743

Due to alternative RNA splicing, several ER isoforms are known to exist. At least three ERalpha and five ERbeta isoforms have been identified. The ERbeta 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 ERalpha isoforms are 36 and 46kDa.[4][5]

Only in fish, but not in humans, an ERgamma receptor has been described.[6]

Genetics[edit]

In humans, the two forms of the estrogen receptor are encoded by different genes, ESR1 and ESR2 on the sixth and fourteenth chromosome (6q25.1 and 14q23.2), respectively.

Distribution[edit]

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

The ERs are regarded to be cytoplasmic receptors in their unliganded state, but visualization research has shown that a fraction of the ERs resides in the nucleus.[11] The "ERα" primary transcript gives rise to several alternatively spliced variants of unknown function.[12]

Binding and functional selectivity[edit]

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.[13][14]

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

Subtype selective estrogen receptor modulators preferentially bind to either the α- or the β-subtype of the receptor. In addition, the different estrogen receptor combinations may respond differently to various ligands, which may translate into tissue selective agonistic and antagonistic effects.[15] The ratio of α- to β- subtype concentration has been proposed to play a role in certain diseases.[16]

The concept of selective estrogen receptor modulators is based on the ability to promote ER interactions with different proteins such as transcriptional coactivator or corepressors. Furthermore, the ratio of coactivator to corepressor protein varies in different tissues.[17] 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[18] but an ER agonist in bone (thereby preventing osteoporosis) and a partial agonist in the endometrium (increasing the risk of uterine cancer) .

Signal transduction[edit]

Since estrogen is a steroidal hormone, it can pass through the phospholipid membranes of the cell, and receptors therefore do not need to be membrane-bound in order to bind with estrogen.

Genomic[edit]

In the absence of hormone, estrogen receptors are largely located in the cytosol. Hormone binding to the receptor triggers a number of events starting with migration of the receptor from the cytosol into the nucleus, dimerization of the receptor, and subsequent binding of the receptor dimer to specific sequences of DNA known as hormone response elements. The DNA/receptor complex then recruits other proteins that are responsible for the transcription of downstream DNA into mRNA and finally protein that results in a change in cell function. Estrogen receptors also occur within the cell nucleus, and both estrogen receptor subtypes have a DNA-binding domain and can function as transcription factors to regulate the production of proteins.

The receptor also interacts with activator protein 1 and Sp-1 to promote transcription, via several coactivators such as PELP-1.[2]

Direct acetylation of the estrogen receptor alpha at the lysine residues in hinge region by p300 regulates transactivation and hormone sensitivity.[19]

Nongenomic[edit]

Some estrogen receptors associate with the cell surface membrane and can be rapidly activated by exposure of cells to estrogen.[20][21]

In addition, some ER may associate with cell membranes by attachment to caveolin-1 and form complexes with G proteins, striatin, receptor tyrosine kinases (e.g., EGFR and IGF-1), and non-receptor tyrosine kinases (e.g., Src).[2][20] Through striatin, some of this membrane bound ER may lead to increased levels of Ca2+ and nitric oxide (NO).[22] Through the receptor tyrosine kinases, signals are sent to the nucleus through the mitogen-activated protein kinase (MAPK/ERK) pathway and phosphoinositide 3-kinase (Pl3K/AKT) pathway.[23] Glycogen synthase kinase-3 (GSK)-3β inhibits transcription by nuclear ER by inhibiting phosphorylation of serine 118 of nuclear ERα. Phosphorylation of GSK-3β removes its inhibitory effect, and this can be achieved by the PI3K/AKT pathway and the MAPK/ERK pathway, via rsk.

17β-Estradiol has been shown to activate the G protein-coupled receptor GPR30.[24] However the subcellular localization and role of this receptor are still object of controversy.[25]

Disease[edit]

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

Cancer[edit]

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:

  • Second, estrogen metabolism produces genotoxic waste.

The result of both processes is disruption of cell cycle, apoptosis and DNA repair, and, therefore, tumour formation. ERα is certainly associated with more differentiated tumours, while evidence that ERβ is involved is controversial. Different versions of the ESR1 gene have been identified (with single-nucleotide polymorphisms) and are associated with different risks of developing breast cancer.[18]

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.[26]

Phytoestrogens such as quercetin can modulate estrogen receptor’s activities in such a way that it may prevent cancers including breasts, prostate, and colon all by promoting apoptosis.[27] Quercetin selectively binds to the estrogen receptor beta (ERβ).[28] This was tested in HeLa cells which were treated with a pure estrogen receptor antagonist which blocked both estradiol and quercetin from inducing the caspase-3 activation.[27] ERβ is expressed in the human colon and activates a specific signal transduction pathway that controls apoptosis in the colon and works by being activated by estradiol and more recently found to possibly be activated by quercetin.[27] Quercetin activates the ERβ along with the apoptotic cascade when caspase-3 is present by the phosphorylation of p38 kinase. In colon cancers and tumors ERβ and its pathway have been proven to be significantly decreased thus allowing the tumors to thrive.[29]

Endocrine therapy for breast cancer involves selective estrogen receptor modulators (SERMS), such as tamoxifen, which behave as ER antagonists in breast tissue, or aromatase inhibitors, such as anastrozole. ER status is used to determine sensitivity of breast cancer lesions to tamoxifen and aromatase inhibitors.[30] Another SERM, raloxifene, has been used as a preventive chemotherapy for women judged to have a high risk of developing breast cancer.[31] 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.[32] 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.[33]

Aging[edit]

Studies in female mice have shown that estrogen receptor-alpha declines in the pre-optic hypothalamus as they grow old. Female mice that were given a calorically restricted diet during the majority of their lives maintained higher levels of ERα in the pre-optic hypothalamus than their non-calorically restricted counterparts.[8]

Obesity[edit]

A dramatic demonstration of the importance of estrogens in the regulation of fat deposition comes from transgenic mice that were genetically engineered to lack a functional aromatase gene. These mice have very low levels of estrogen and are obese.[34] Obesity was also observed in estrogen deficient female mice lacking the follicle-stimulating hormone receptor.[35] The effect of low estrogen on increased obesity has been linked to estrogen receptor alpha.[36]

Research history[edit]

Estrogen receptors were first identified by Elwood V. Jensen at the University of Chicago in 1958,[37][38] for which Jensen was awarded the Lasker Award.[39] 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.[40]

References[edit]

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