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Proteins activated by the hormone estrogen

Estrogen receptors (ERs) are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen (17β estradiol). Two classes of ER exist: nuclear estrogen receptors (ERα and ERβ), which are members of the nuclear receptor family of intracellular receptors, and membrane estrogen receptors (mERs) (GPER (GPR30), ER X, and Gq mER), which are mostly 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. As hormone receptors for sex steroids (steroid hormone receptors), ERs, androgen receptors (ARs), and progesterone receptors (PRs) are important in sexual maturation and gestation.

There are two different forms of the estrogen receptor, usually referred to as α and β, each encoded by a separate gene ( and , 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. Estrogen receptor alpha and beta show significant overall sequence homology, and both are composed of five domains designated A/B through F (listed from the N to C terminus; amino acid sequence numbers refer to human ER). 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. 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. Only in fish, but not in humans, an ERγ receptor has been described.

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

Endogenous estrogens (e. g., estradiol, estrone, estriol, estetrol)
Natural estrogens (e. g., conjugated estrogens)
Synthetic estrogens (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)

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.

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

Some estrogen receptors associate with the cell surface membrane and can be rapidly activated by exposure of cells to estrogen. 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). 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. 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. However the subcellular localization and role of this receptor are still object of controversy.

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 cells, 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 polymorphisms) and are associated with different risks of developing breast cancer. 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. Another SERM, raloxifene, has been used as a preventive chemotherapy for women judged to have a high risk of developing breast cancer. 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. 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.

The metabolic effects of estrogen in postmenopausal women has been linked to the genetic polymorphism of estrogen receptor beta (ER β).

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. Obesity was also observed in estrogen deficient female mice lacking the follicle stimulating hormone receptor. The effect of low estrogen on increased obesity has been linked to estrogen receptor alpha.

SERMs are also being studied for the treatment of uterine fibroids and endometriosis.

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 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 gonads produce markedly higher levels of estrogen for individuals with EIS (119–272 pg/mL XY and 750 3,500 pg/mL XX, see average levels) however no feminizing effects occur.

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