Estrogen receptor

An estrogen receptor (ER) is a nuclear receptor for estrogens such as estradiol (the main endogenous human estrogen). Estrogen receptors are intracellular proteins like other steroid hormone receptors. Some estrogen receptors associate with the cell surface membrane and can be rapidly activated by exposure of cells to estrogen. 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. Both receptors also have functions independent of DNA binding.

Proteomics
The two different estrogen receptor proteins produced from the ESR1 and ESR2 genes are usually called the α and β receptors. The estrogen receptors form dimers, and there the two different receptor subtypes can form mixed dimers in the presence of ligands. Hence, there are three combinations: ERα (αα), ERβ (ββ) and ERαβ (αβ). Different tissues express the subtypes in different proportions, and therefore have different responses to stimulation.

Both receptors show some overall homology, and are composed of seven domains (listed from N- to C-; numbers refer to human ER, and may vary):



Genetics
The two chains are coded by different genes, ESR1 and ESR2 on the sixth and fourteenth chromosome (6q25.1 and 14q), respectively.

Distribution
All the ERs are widely distributed.
 * The ERα is found in endometrium, breast cancer cells, ovarian stroma cells and the hypothalamus.
 * The ERβ has been documented in kidney, brain, bone, heart, lungs, intestinal mucosa, prostate, and endothelial cells.

Binding affinity
Different estrogenic compounds have different binding affinities for alpha and beta ERs:


 * 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.

The concept of selective estrogen receptor modulators is based on the ability to selectively activate (or block) one type of ER or to promote ER interactions with different proteins such as transcriptional co-activator or co-repressor proteins.

Additionally, the different estrogen receptor combinations respond differently to various antagonists, and some compounds have partially agonistic and antagonistic effects, depending on the tissue. Tamoxifen, for example, is an ER agonist in bone and uterus, but antagonist in breast tissue, and is therefore used as a breast cancer treatment.

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.

Nuclear
One of the major mechanisms of estrogen is to initiate the production of proteins. Estrogen receptors are therefore located in the nucleus where, when bound with estrogen as an estrogen-ER complex, bind to the estrogen response element to promote transcription.

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

Cytosolic
Some ER is attached to the cell membrane by caveolin-1, and forms 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. The 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 evidence supports a combination of both:
 * 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.

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