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Estrogen receptor alpha (ERα), also known as NR3A1 (nuclear receptor subfamily 3, group A, member 1), is one of two main types of estrogen receptor, a nuclear receptor (mainly found as a chromatin-binding protein) that is activated by the sex hormone estrogen. In humans, ERα is encoded by the
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
''ESR1'' (EStrogen Receptor 1).


Structure

The estrogen receptor (ER) is a ligand-activated
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...
composed of several domains important for hormone binding, DNA binding, and activation of transcription. Alternative splicing results in several ESR1
mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...
transcripts, which differ primarily in their 5-prime untranslated regions. The translated receptors show less variability.


Ligands


Agonists


Non-selective

* Endogenous estrogens (e.g., estradiol, estrone, estriol, estetrol) * Natural estrogens (e.g., conjugated equine estrogens) * Synthetic estrogens (e.g., ethinylestradiol, diethylstilbestrol)


Selective

Agonists of ERα selective over
ERβ Estrogen receptor beta (ERβ) also known as NR3A2 (nuclear receptor subfamily 3, group A, member 2) is one of two main types of estrogen receptor—a nuclear receptor which is activated by the sex hormone estrogen. In humans ERβ is encoded by t ...
include: * Propylpyrazoletriol (PPT) * 16α-LE2 (Cpd1471) * 16α-IE2 * ERA-63 (ORG-37663) * SKF-82,958 – also a D1-like receptor full agonist * (R,R)-Tetrahydrochrysene ((R,R)-THC) – actually not selective over ERβ, but rather an antagonist instead of an agonist of ERβ


Mixed

* Phytoestrogens (e.g., coumestrol, daidzein, genistein, miroestrol) * Selective estrogen receptor modulators (e.g., tamoxifen, clomifene, raloxifene)


Antagonists


Non-selective

* Antiestrogens (e.g., fulvestrant, ICI-164384, ethamoxytriphetol)


Selective

Antagonists of ERα selective over ERβ include: * Methylpiperidinopyrazole (MPP)


Affinities


Tissue distribution and function

ERα plays a role in the physiological development and function of a variety of organ systems to varying degrees, including the reproductive, central nervous, skeletal, and cardiovascular systems. Accordingly, ERα is widely expressed throughout the body, including the
uterus The uterus (from Latin ''uterus'', : uteri or uteruses) or womb () is the hollow organ, organ in the reproductive system of most female mammals, including humans, that accommodates the embryonic development, embryonic and prenatal development, f ...
and ovary, male reproductive organs, mammary gland,
bone A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, ...
,
heart The heart is a muscular Organ (biology), organ found in humans and other animals. This organ pumps blood through the blood vessels. The heart and blood vessels together make the circulatory system. The pumped blood carries oxygen and nutrie ...
, hypothalamus, pituitary gland, liver, lung, kidney, spleen, and adipose tissue. The development and function of these tissues is disrupted in animal models lacking active ERα genes, such as the ERα knockout mouse (ERKO), providing a preliminary understanding of ERα function at specific target organs.


Uterus and ovary

ERα is essential in the maturation of the female reproductive phenotype. In the absence of ERα, the ERKO mouse develops an adult
uterus The uterus (from Latin ''uterus'', : uteri or uteruses) or womb () is the hollow organ, organ in the reproductive system of most female mammals, including humans, that accommodates the embryonic development, embryonic and prenatal development, f ...
, indicating that ERα may not mediate the initial growth of the uterus. However, ERα plays a role in the completion of this development, and the subsequent function of the tissue. Activation of ERα is known to trigger cell proliferation in the uterus. The
uterus The uterus (from Latin ''uterus'', : uteri or uteruses) or womb () is the hollow organ, organ in the reproductive system of most female mammals, including humans, that accommodates the embryonic development, embryonic and prenatal development, f ...
of female ERKO mice is hypoplastic, suggesting that ERα mediates mitosis and differentiation in the uterus in response to estrogen stimulation. Similarly, prepubertal female ERKO mice develop
ovaries The ovary () is a gonad in the female reproductive system that produces ova; when released, an ovum travels through the fallopian tube/oviduct into the uterus. There is an ovary on the left and the right side of the body. The ovaries are endocr ...
that are nearly indistinguishable from those of their wildtype counterparts. However, as the ERKO mice mature they progressively present an abnormal ovarian phenotype in both physiology and function. Specifically, female ERKO mice develop enlarged
ovaries The ovary () is a gonad in the female reproductive system that produces ova; when released, an ovum travels through the fallopian tube/oviduct into the uterus. There is an ovary on the left and the right side of the body. The ovaries are endocr ...
containing hemorrhagic follicular cysts, which also lack the corpus luteum, and therefore do not ovulate. This adult ovarian phenotype suggests that in the absence of ERα, estrogen is no longer able to perform negative feedback on the hypothalamus, resulting in chronically elevated LH levels and constant ovarian stimulation. These results identify a pivotal role for ERα in the hypothalamus, in addition to its role in the estrogen-driven maturation through theca and interstitial cells of the ovary.


Male reproductive organs

ERα is similarly essential in the maturation and maintenance of the male reproductive phenotype, as male ERKO mice are infertile and present undersized testes. The integrity of testicular structures of ERKO mice, such as the seminiferous tubules of the testes and the seminiferous epithelium, declines over time. Furthermore, the reproductive performance of male ERKO mice is hindered by abnormalities in sexual physiology and
behavior Behavior (American English) or behaviour (British English) is the range of actions of Individual, individuals, organisms, systems or Artificial intelligence, artificial entities in some environment. These systems can include other systems or or ...
, such as impaired spermatogenesis and loss of intromission and ejaculatory responses.


Mammary gland

Estrogen stimulation of ERα is known to stimulate cell proliferation in breast tissue. ERα is thought to be responsible for pubertal development of the adult phenotype, through mediation of mammary gland response to estrogens. This role is consistent with the abnormalities of female ERKO mice: the epithelial ducts of female ERKO mice fail to grow beyond their pre-pubertal length, and lactational structures do not develop. As a result, the functions of the mammary gland—including both lactation and release of prolactin—are greatly impaired in ERKO mice.


Bone

Though its expression in
bone A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, ...
is moderate, ERα is known to be responsible for maintenance of bone integrity. It is hypothesized that estrogen stimulation of ERα may trigger the release of growth factors, such as epidermal growth factor or insulin-like growth factor-1, which in turn regulate bone development and maintenance. Accordingly, male and female ERKO mice exhibit decreased bone
length Length is a measure of distance. In the International System of Quantities, length is a quantity with Dimension (physical quantity), dimension distance. In most systems of measurement a Base unit (measurement), base unit for length is chosen, ...
and
size Size in general is the Magnitude (mathematics), magnitude or dimensions of a thing. More specifically, ''geometrical size'' (or ''spatial size'') can refer to three geometrical measures: length, area, or volume. Length can be generalized ...
.


Brain

Estrogen signaling through ERα appears to be responsible for various aspects of central nervous development, such as synaptogenesis and synaptic remodeling. In the brain, ERα is found in hypothalamus, and preoptic area, and arcuate nucleus, all three of which have been linked to reproductive behavior, and the masculinization of the mouse brain appears to take place through ERα function. Furthermore, studies in models of psychopathology and neurodegenerative disease states suggest that estrogen receptors mediate the neuroprotective role of estrogen in the brain. Finally, ERα appears to mediate positive feedback effects of estrogen on the brain's secretion of GnRH and LH, by way increasing expression of kisspeptin in neurons of the arcuate nucleus and anteroventral periventricular nucleus. Although classical studies have suggested that negative feedback effects of estrogen also operate through ERα, female mice lacking ERα in kisspeptin-expressing neurons continue to demonstrate a degree of negative feedback response.


Clinical significance

Estrogen insensitivity syndrome is a very rare condition characterized by a defective ERα that is insensitive to estrogens. The clinical presentation of a female was observed to include absence of breast development and other female
secondary sexual characteristic A secondary sex characteristic is a physical characteristic of an organism that is related to or derived from its sex, but not directly part of its reproductive system. In humans, these characteristics typically start to appear during puberty ...
s at puberty, hypoplastic
uterus The uterus (from Latin ''uterus'', : uteri or uteruses) or womb () is the hollow organ, organ in the reproductive system of most female mammals, including humans, that accommodates the embryonic development, embryonic and prenatal development, f ...
, primary amenorrhea, enlarged multicystic ovaries and associated lower abdominal pain, mild hyperandrogenism (manifested as cystic acne), and delayed bone maturation as well as an increased rate of bone turnover. The clinical presentation in a male was reported to include lack of epiphyseal closure, tall stature, osteoporosis, and poor sperm viability. Both individuals were completely insensitive to exogenous estrogen treatment, even with high doses. Genetic polymorphisms in the gene encoding the ERα have been associated with breast cancer in women, gynecomastia in men and dysmenorrhea. In patients with breast cancer, mutations in the gene encoding ERα (ESR1) have been associated with resistance to endocrine therapy, especially aromatase inhibitors.


Coactivators

Coactivators of ER-α include: * SRC-1 * AIB1 – amplified in breast 1 * PELP-1 – Proline-, glutamic acid-, leucine-rich protein 1


Interactions

Estrogen receptor alpha has been shown to interact with: * AKAP13 * AHR * BRCA1 * CAV1 * CCNC * CDC25B * CEBPB * COBRA1 * COUP-TFI * CREBBP * CRSP3 * Cyclin D1 * DNTTIP2 * EP300 * ESR2 * FOXO1 * GREB1 * GTF2H1 * HSPA1A * HSPA8 * HSP90AA1 * ISL1 * JARID1A * MVP * MED1 * MED12 * MED14 * MED16 * MED24 * MED6 * MGMT * MNAT1 * MTA1 * NCOA6 * NCOA1 * NCOA2 * NCOA3 * NRIP1 * PDLIM1 * POU4F1 * POU4F2 * PRDM2 * PRMT2 * RBM39 * RNF12 * SAFB * SAFB2 * SHC1 * SHP * SMARCA4 * SMARCE1 * Src * TR2 * TR4 * TDG * TRIM24 and * XBP1.


References


Further reading

* * * * * * * * * * * * * * * * * * * *


External links

* * {{Estrogen receptor modulators Intracellular receptors Transcription factors