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
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External links
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{{Estrogen receptor modulators
Intracellular receptors
Transcription factors