Estrogen receptor

The estrogen receptor (ER) is a member of the nuclear hormone family of intracellular receptors which is activated by the hormone 17β-estradiol. The main function of the estrogen receptor is as a DNA binding transcription factor which regulates gene expression. However the estrogen receptor also has additional functions independent of DNA binding.

Proteomics
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 seven domains (listed from the N- to C-terminus; amino acid sequence numbers refer to human ER):

Genetics
The two forms of the estrogen receptor are encoded by different genes, and  on the sixth and fourteenth chromosome (6q25.1 and 14q), respectively.

Distribution
Both ERs are widely expressed in different tissue types, however there are some notable differences in their expression patterns:
 * The ERα is found in endometrium, breast cancer cells, ovarian stroma cells and in the hypothalamus.
 * The expression of the ERβ protein has been documented in kidney, brain, bone, heart, lungs, intestinal mucosa, prostate, and endothelial cells.

Binding and Functional Selectivity


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


 * 17-beta-estradiol binds equally well to both receptors
 * estrone and raloxifene bind preferentially to the alpha receptor
 * estriol and genistein to the beta receptor

Subtype selective estrogen receptor modulators preferentially bind to either the α- or β-subtype of the receptor. Additionally, the different estrogen receptor combinations may respond differently to various ligands which may translate into tissue selective agonistic and antagonistic effects.

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. 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 but an ER agonist in bone (thereby preventing osteoporosis) and an agonist in the endometrium (increasing the risk of uterine cancer).

Signal transduction
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
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 subsequently binding of the receptor dimer to specific sequences of DNA known as hormone response elements. The DNA/receptor complex then recruits other proteins which are responsible for the transcription of downstream DNA into mRNA and finally protein which 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.

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

Additionally 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 striatin, some of this membrane bound ER may lead to increased levels of Ca 2+ and nitric oxide (NO). 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.

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.

Cancer
Estrogen receptors are overexpressed in around 70% of breast cancer cases, referred to as "ER positive". Two hypotheses have been proposed to explain why this causes tumorigenesis, and the available evidence suggests that both mechanisms contribute:
 * Firstly, binding of estrogen to the ER stimulates proliferation of mammary cells, with the resulting increase in cell division and DNA replication leading to mutations.
 * Secondly, 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. Another chemotherapeutic anti-estrogen, ICI 182,780 (Faslodex) which acts as a complete antagonist also promotes degradation of the estrogen receptor.

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.

Obesity
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. 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.

Research history
Estrogen receptors were first identified by Elwood V. Jensen at the University of Chicago in the 1950s, for which Jensen was awarded the Lasker Award. The gene for a second estrogen receptor (ERβ) was identified in 1996.