The estrogen receptor (ER) is a member of the nuclear hormone family of intracellular receptors which is activated by the hormone 17β-estradiol (estrogen). 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.
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 only transactivate transcription 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. Only in fish, but not in humans, an ERgamma receptor has been described.
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.
The ER's helix 12 domain plays a crucial role in determining interactions with coactivators and corepressors and thereby the respective agonist or antagonist effect of the ligand.
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 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 ratio of α- to β- subtype concentration has been proposed to play a role in certain diseases.
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) .
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 Ca2+ 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.
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 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.