Estrogen receptor
Encyclopedia
Estrogen receptor refers to a group of receptor
s that are activated by the hormone
17β-estradiol
(estrogen). Two types of estrogen receptor exist: ER, which is a member of the nuclear hormone
family of intracellular
receptors, and the estrogen G protein-coupled receptor GPR30
(GPER), which is a G protein-coupled receptor
. This article refers to the nuclear hormone receptor ER.
The main function of the estrogen receptor is as a DNA-binding transcription factor
that regulates gene expression. However, the estrogen receptor has additional functions independent of DNA binding.
and β
, each encoded by a separate gene ( and , respectively). Hormone-activated estrogen receptors form dimer
s, 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 five domains
(listed from the N- to C-terminus; amino acid
sequence numbers refer to human ER):(A-F domain)
The N-terminal A/B domain is able to transactivate
gene transcription in the absence of bound ligand
(e.g., the estrogen hormone). While this region is able to activate gene transcription without ligand, this activation is weak and more selective compared to the activation provided by the E domain. The C domain, also known as the DNA-binding domain
, binds to estrogen response element
s in DNA. The D domain is a hinge region that connects the C and E domains. The E domain contains the ligand binding cavity as well as binding sites for coactivator
and corepressor
proteins. The E-domain in the presence of bound ligand is able to activate gene transcription. The C-terminal F domain function is not entirely clear and is variable in length.
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 transactivate transcription only 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.
s, and on the sixth and fourteenth chromosome
(6q25.1 and 14q23.2), respectively.
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 "ERα" primary transcript gives rise to several alternatively spliced variants of unknown function.
Different ligand
s may differ in their affinity for alpha and beta isoforms of the estrogen receptor:
Subtype selective estrogen receptor modulator
s preferentially bind to either the α- or the β-subtype of the receptor. In addition, 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 modulator
s is based on the ability to promote ER interactions with different proteins such as transcriptional
coactivator
or corepressor
s. 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 a partial agonist in the endometrium
(increasing the risk of uterine cancer
) .
al 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.
. 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 subsequent binding of the receptor dimer to specific sequences of DNA known as hormone response element
s. The DNA/receptor complex then recruits other proteins that are responsible for the transcription
of downstream DNA into mRNA and finally protein that 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 factor
s to regulate the production of protein
s.
The receptor also interacts with activator protein 1
and Sp-1 to promote transcription, via several coactivators such as PELP-1
.
In addition, some ER may associate with cell membranes by attachment to caveolin-1
and form complexes with G protein
s, striatin
, receptor tyrosine kinase
s (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
.
17β-Estradiol has been shown to activate the G protein-coupled receptor
GPR30
. However the subcellular localization and role of this receptor are still object of controversy.
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:
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 modulator
s (SERMS), such as tamoxifen
, which behave as ER antagonists in breast tissue, or aromatase inhibitors, such as anastrozole
. 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.
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.
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.
at the University of Chicago
in 1958, for which Jensen was awarded the Lasker Award
. The gene for a second estrogen receptor (ERβ) was identified in 1996 by Kuiper et al. in rat prostate and ovary using degenerate ERalpha primers.
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
s that are activated by the hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
17β-estradiol
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
(estrogen). Two types of estrogen receptor exist: ER, which is a member of the nuclear hormone
Nuclear receptor
In the field of molecular biology, nuclear receptors are a class of proteins found within cells that are responsible for sensing steroid and thyroid hormones and certain other molecules...
family of intracellular
Intracellular
Not to be confused with intercellular, meaning "between cells".In cell biology, molecular biology and related fields, the word intracellular means "inside the cell".It is used in contrast to extracellular...
receptors, and the estrogen G protein-coupled receptor GPR30
GPR30
G-protein coupled estrogen receptor 1 also known as the membrane estrogen receptor or G-protein coupled receptor 30 is a G protein-coupled receptor that in humans is encoded by the GPER gene...
(GPER), which is a G protein-coupled receptor
G protein-coupled receptor
G protein-coupled receptors , also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors , comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal...
. This article refers to the nuclear hormone receptor ER.
The main function of the estrogen receptor is as a DNA-binding transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
that regulates gene expression. However, the estrogen receptor has additional functions independent of DNA binding.
Proteomics
There are two different forms of the estrogen receptor, usually referred to as αEstrogen receptor alpha
Estrogen receptor alpha , also known as NR3A1 , is a nuclear receptor that is activated by the sex hormone estrogen...
and β
Estrogen receptor beta
Estrogen receptor beta , also known as NR3A2 , is a nuclear receptor which is activated by the sex hormone estrogen. In humans, ER-β is encoded by the ESR2 gene.- Function :...
, each encoded by a separate gene ( and , respectively). Hormone-activated estrogen receptors form dimer
Protein dimer
In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...
s, 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 five domains
Protein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
(listed from the N- to C-terminus; amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
sequence numbers refer to human ER):(A-F domain)
Transactivation
In molecular biology and genetics, transactivation is an increased rate of gene expression triggered either by biological processes or by artificial means.- Natural transactivation :...
gene transcription in the absence of bound ligand
Ligand (biochemistry)
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as ionic bonds, hydrogen...
(e.g., the estrogen hormone). While this region is able to activate gene transcription without ligand, this activation is weak and more selective compared to the activation provided by the E domain. The C domain, also known as the DNA-binding domain
DNA-binding domain
A DNA-binding domain is an independently folded protein domain that contains at least one motif that recognizes double- or single-stranded DNA. A DBD can recognize a specific DNA sequence or have a general affinity to DNA...
, binds to estrogen response element
Response element
Response elements are short sequences of DNA within a gene promoter region that are able to bind a specific transcription factor and regulate transcription of genes.-Examples:Examples of response elements include:*Hormone response element...
s in DNA. The D domain is a hinge region that connects the C and E domains. The E domain contains the ligand binding cavity as well as binding sites for coactivator
Coactivator (genetics)
A coactivator is a protein that increases gene expression by binding to an activator which contains a DNA binding domain. The coactivator is unable to bind DNA by itself....
and corepressor
Corepressor (genetics)
In molecular genetics, a corepressor is a substance that inhibits the expression of genes. A corepressor downregulates the expression of genes not through direct interaction with a gene promoter , but rather indirectly through interaction with repressor proteins that in turn bind to the...
proteins. The E-domain in the presence of bound ligand is able to activate gene transcription. The C-terminal F domain function is not entirely clear and is variable in length.
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 transactivate transcription only 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.
Genetics
The two forms of the estrogen receptor are encoded by different geneGene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s, and on the sixth and fourteenth chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
(6q25.1 and 14q23.2), 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 endometriumEndometrium-Function:The endometrium is the innermost glandular layer and functions as a lining for the uterus, preventing adhesions between the opposed walls of the myometrium, thereby maintaining the patency of the uterine cavity. During the menstrual cycle or estrous cycle, the endometrium grows to a...
, breast cancerBreast cancerBreast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
cells, ovarian stroma cells, and the hypothalamusHypothalamusThe Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
. In males, ERα protein is found in the epithelium of the efferent ductsEfferent ductsThe efferent ducts connect the rete testis with the initial section of the epididymis.There are two basic designs for efferent ductule structure:...
. - The expression of the ERβ protein has been documented in kidneyKidneyThe kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
, brainBrainThe brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
, boneBoneBones are rigid organs that constitute part of the endoskeleton of vertebrates. They support, and protect the various organs of the body, produce red and white blood cells and store minerals. Bone tissue is a type of dense connective tissue...
, heartHeartThe heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...
, lungs, intestinalIntestineIn human anatomy, the intestine is the segment of the alimentary canal extending from the pyloric sphincter of the stomach to the anus and, in humans and other mammals, consists of two segments, the small intestine and the large intestine...
mucosa, prostateProstateThe prostate is a compound tubuloalveolar exocrine gland of the male reproductive system in most mammals....
, and endothelialEndotheliumThe endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...
cells.
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 "ERα" primary transcript gives rise to several alternatively spliced variants of unknown function.
Binding and functional selectivity
The ER's helix 12 domain plays a crucial role in determining interactions with coactivators and corepressors and, therefore, the respective agonist or antagonist effect of the ligand.Different ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
s may differ in their affinity for alpha and beta isoforms of the estrogen receptor:
- 17-beta-estradiolEstradiolEstradiol is a sex hormone. Estradiol is abbreviated E2 as it has 2 hydroxyl groups in its molecular structure. Estrone has 1 and estriol has 3 . Estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect...
binds equally well to both receptors - estroneEstroneEstrone is an estrogenic hormone secreted by the ovary as well as adipose tissue.Estrone is one of several natural estrogens, which also include estriol and estradiol...
, and raloxifeneRaloxifeneRaloxifene is an oral selective estrogen receptor modulator that has estrogenic actions on bone and anti-estrogenic actions on the uterus and breast...
bind preferentially to the alpha receptor - estriolEstriolEstriol is one of the three main estrogens produced by the human body.-Synthesis:Estriol is only produced in significant amounts during pregnancy as it is made by the placenta from 16-Hydroxydehydroepiandrosterone sulfate , an androgen steroid made in the fetal liver and adrenal glands.The human...
, and genisteinGenisteinGenistein is one of several known isoflavones. Isoflavones, such as genistein and daidzein, are found in a number of plants including lupin, fava beans, soybeans, kudzu, and psoralea being the primary food source, also in the medicinal plant, Flemingia vestita and coffee Besides functioning as...
to the beta receptor
Subtype selective estrogen receptor modulator
Selective estrogen receptor modulator
Selective Estrogen Receptor Modulators are a class of compounds that act on the estrogen receptor. A characteristic that distinguishes these substances from pure receptor agonists and antagonists is that their action is different in various tissues, thereby granting the possibility to selectively...
s preferentially bind to either the α- or the β-subtype of the receptor. In addition, 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 modulator
Selective estrogen receptor modulator
Selective Estrogen Receptor Modulators are a class of compounds that act on the estrogen receptor. A characteristic that distinguishes these substances from pure receptor agonists and antagonists is that their action is different in various tissues, thereby granting the possibility to selectively...
s is based on the ability to promote ER interactions with different proteins such as transcriptional
Transcription coregulator
In molecular biology and genetics, transcription coregulators are proteins that interact with transcription factors to either activate or repress the transcription of specific genes. Transcription coregulators that activate gene transcription are referred to as coactivators while those that...
coactivator
Coactivator (genetics)
A coactivator is a protein that increases gene expression by binding to an activator which contains a DNA binding domain. The coactivator is unable to bind DNA by itself....
or corepressor
Corepressor (genetics)
In molecular genetics, a corepressor is a substance that inhibits the expression of genes. A corepressor downregulates the expression of genes not through direct interaction with a gene promoter , but rather indirectly through interaction with repressor proteins that in turn bind to the...
s. 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
Breast
The breast is the upper ventral region of the torso of a primate, in left and right sides, which in a female contains the mammary gland that secretes milk used to feed infants.Both men and women develop breasts from the same embryological tissues...
and is, therefore, used as a breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
treatment but an ER agonist in bone
Bone
Bones are rigid organs that constitute part of the endoskeleton of vertebrates. They support, and protect the various organs of the body, produce red and white blood cells and store minerals. Bone tissue is a type of dense connective tissue...
(thereby preventing osteoporosis
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
) and a partial agonist in the endometrium
Endometrium
-Function:The endometrium is the innermost glandular layer and functions as a lining for the uterus, preventing adhesions between the opposed walls of the myometrium, thereby maintaining the patency of the uterine cavity. During the menstrual cycle or estrous cycle, the endometrium grows to a...
(increasing the risk of uterine cancer
Uterine cancer
The term uterine cancer may refer to any of several different types of cancer which occur in the uterus, namely:*Uterine sarcomas: sarcomas of the myometrium, or muscular layer of the uterus, are most commonly leiomyosarcomas.*Endometrial cancer:...
) .
Signal transduction
Since estrogen is a steroidSteroid
A steroid is a type of organic compound that contains a characteristic arrangement of four cycloalkane rings that are joined to each other. Examples of steroids include the dietary fat cholesterol, the sex hormones estradiol and testosterone, and the anti-inflammatory drug dexamethasone.The core...
al 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 cytosolCytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
. 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 subsequent binding of the receptor dimer to specific sequences of DNA known as hormone response element
Hormone response element
A hormone response element is a response element for hormones, a short sequence of DNA within the promoter of a gene that is able to bind a specific hormone receptor complex and therefore regulate transcription...
s. The DNA/receptor complex then recruits other proteins that are responsible for the transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
of downstream DNA into mRNA and finally protein that results in a change in cell function. Estrogen receptors also occur within the cell nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
, and both estrogen receptor subtypes have a DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
-binding domain
Protein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
and can function as transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
s to regulate the production of protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s.
The receptor also interacts with activator protein 1
AP-1 (transcription factor)
In the field of molecular biology, the activator protein 1 is a transcription factor which is a heterodimeric protein composed of proteins belonging to the c-Fos, c-Jun, ATF and JDP families. It regulates gene expression in response to a variety of stimuli, including cytokines, growth factors,...
and Sp-1 to promote transcription, via several coactivators such as PELP-1
PELP-1
PELP-1 is a transcriptional corepressor for nuclear receptors such as glucocorticoid receptors and a coactivator for estrogen receptors.-Activation of protein kinases:...
.
Nongenomic
Some estrogen receptors associate with the cell surface membrane and can be rapidly activated by exposure of cells to estrogen.In addition, some ER may associate with cell membranes by attachment to caveolin-1
Caveolin
Caveolins are a family of integral membrane proteins which are the principal components of caveolae membranes and involved in receptor-independent endocytosis. Caveolins may act as scaffolding proteins within caveolar membranes by compartmentalizing and concentrating signaling molecules...
and form complexes with G protein
G protein
G proteins are a family of proteins involved in transmitting chemical signals outside the cell, and causing changes inside the cell. They communicate signals from many hormones, neurotransmitters, and other signaling factors. G protein-coupled receptors are transmembrane receptors...
s, striatin
STRN
Striatin is a protein that in humans is encoded by the STRN gene.-Interactions:STRN has been shown to interact with STK25, PDCD10, CTTNBP2, TRAF3IP3, STRN3, MOBKL3, STK24, PPP2CA, RP6-213H19.1, PPP2R1A, CTTNBP2NL and FAM40A.-Further reading:...
, receptor tyrosine kinase
Tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....
s (e.g., EGFR
Epidermal growth factor receptor
The epidermal growth factor receptor is the cell-surface receptor for members of the epidermal growth factor family of extracellular protein ligands...
and IGF-1), and non-receptor tyrosine kinases (e.g., Src
Src (gene)
Proto-oncogene tyrosine-protein kinase Src is an enzyme that in humans is encoded by the SRC gene.Src is a proto-oncogene encoding a tyrosine kinase originally discovered by J. Michael Bishop and Harold E. Varmus, for which they won the 1989 Nobel Prize in Physiology or Medicine. It belongs to a...
). Through striatin, some of this membrane bound ER may lead to increased levels of Ca2+
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
and nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
(NO). Through the receptor tyrosine kinases, signals are sent to the nucleus through the mitogen-activated protein kinase
Mitogen-activated protein kinase
Mitogen-activated protein kinases are serine/threonine-specific protein kinases that respond to extracellular stimuli and regulate various cellular activities, such as gene expression, mitosis, differentiation, proliferation, and cell survival/apoptosis.-Activation:MAP kinases are activated...
(MAPK/ERK) pathway and phosphoinositide 3-kinase
Phosphoinositide 3-kinase
Phosphatidylinositol 3-kinases are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. In response to lipopolysaccharide, PI3K phosphorylates p65, inducing...
(Pl3K/AKT
AKT
Akt, also known as Protein Kinase B , is a serine/threonine protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration.-Family members:...
) pathway. Glycogen synthase kinase-3
GSK-3
Glycogen synthase kinase 3 is a serine/threonine protein kinase that mediates the addition of phosphate molecules on certain serine and threonine amino acids in particular cellular substrates...
(GSK)-3β inhibits transcription by nuclear ER by inhibiting phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
of serine
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
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
Ribosomal s6 kinase
In molecular biology, ribosomal s6 kinase is a family of protein kinases involved in signal transduction. There are two subfamilies of rsk, p90rsk, also known as MAPK-activated protein kinase-1 , and p70rsk, also known as S6-H1 Kinase or simply S6 Kinase. There are three variants of p90rsk in...
.
17β-Estradiol has been shown to activate the G protein-coupled receptor
G protein-coupled receptor
G protein-coupled receptors , also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors , comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal...
GPR30
GPR30
G-protein coupled estrogen receptor 1 also known as the membrane estrogen receptor or G-protein coupled receptor 30 is a G protein-coupled receptor that in humans is encoded by the GPER gene...
. However the subcellular localization and role of this receptor are still object of controversy.
Disease
Cancer
Estrogen receptors are over-expressed in around 70% of breast cancerBreast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
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:
- First, binding of estrogen to the ER stimulates proliferation of mammary cellMammary glandA mammary gland is an organ in mammals that produces milk to feed young offspring. Mammals get their name from the word "mammary". In ruminants such as cows, goats, and deer, the mammary glands are contained in their udders...
s, with the resulting increase in cell divisionCell divisionCell division is the process by which a parent cell divides into two or more daughter cells . Cell division is usually a small segment of a larger cell cycle. This type of cell division in eukaryotes is known as mitosis, and leaves the daughter cell capable of dividing again. The corresponding sort...
and DNA replicationDNA replicationDNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...
, leading to mutations.
- Second, estrogen metabolism produces genotoxicGenotoxicIn genetics, genotoxicity describes a deleterious action on a cell's genetic material affecting its integrity. This includes both certain chemical compounds and certain types of radiation....
waste.
The result of both processes is disruption of cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
, apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
and DNA repair
DNA repair
DNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as UV light and radiation can cause DNA damage, resulting in as many as 1...
, 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 modulator
Selective estrogen receptor modulator
Selective Estrogen Receptor Modulators are a class of compounds that act on the estrogen receptor. A characteristic that distinguishes these substances from pure receptor agonists and antagonists is that their action is different in various tissues, thereby granting the possibility to selectively...
s (SERMS), such as tamoxifen
Tamoxifen
Tamoxifen is an antagonist of the estrogen receptor in breast tissue via its active metabolite, hydroxytamoxifen. In other tissues such as the endometrium, it behaves as an agonist, hence tamoxifen may be characterized as a mixed agonist/antagonist...
, which behave as ER antagonists in breast tissue, or aromatase inhibitors, such as anastrozole
Anastrozole
Anastrozole is an aromatase-inhibiting drug approved for treatment of breast cancer after surgery, as well as for metastasis in both pre and post-menopausal women. The severity of breast cancer is increased by estrogen, as sex hormones cause hyperplasia, and differentiation at estrogen receptor...
. ER status is used to determine sensitivity of breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
lesions to tamoxifen and aromatase inhibitors. Another SERM, raloxifene
Raloxifene
Raloxifene is an oral selective estrogen receptor modulator that has estrogenic actions on bone and anti-estrogenic actions on the uterus and breast...
, 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
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
, ovarian cancer
Ovarian cancer
Ovarian cancer is a cancerous growth arising from the ovary. Symptoms are frequently very subtle early on and may include: bloating, pelvic pain, difficulty eating and frequent urination, and are easily confused with other illnesses....
, colon cancer, prostate cancer
Prostate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
, and endometrial cancer
Endometrial cancer
Endometrial cancer refers to several types of malignancies that arise from the endometrium, or lining, of the uterus. Endometrial cancers are the most common gynecologic cancers in the United States, with over 35,000 women diagnosed each year. The incidence is on a slow rise secondary to the...
. 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.
Aging
Studies in female mice have shown that estrogen receptor-alpha declines in the pre-optic hypothalamusHypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
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.
Obesity
A dramatic demonstration of the importance of estrogens in the regulation of fat deposition comes from transgenic miceGenetically modified organism
A genetically modified organism or genetically engineered organism is an organism whose genetic material has been altered using genetic engineering techniques. These techniques, generally known as recombinant DNA technology, use DNA molecules from different sources, which are combined into one...
that were genetically engineered to lack a functional aromatase
Aromatase
Aromatase is an enzyme responsible for a key step in the biosynthesis of estrogens. It is a member of the cytochrome P450 superfamily , which are monooxygenases that catalyze many reactions involved in steroidogenesis. In particular, aromatase is responsible for the aromatization of androgens into...
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
Follicle-stimulating hormone
Follicle-stimulating hormone is a hormone found in humans and other animals. It is synthesized and secreted by gonadotrophs of the anterior pituitary gland. FSH regulates the development, growth, pubertal maturation, and reproductive processes of the body. FSH and Luteinizing hormone act...
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. JensenElwood V. Jensen
Elwood V. Jensen is the Distinguished University Professor, George and Elizabeth Wile Chair in Cancer Research at the University of Cincinnati College of Medicine's Vontz Center for Molecular Studies. In 2004 he received the Albert Lasker Award for Basic Medical Research for his research on...
at the University of Chicago
University of Chicago
The University of Chicago is a private research university in Chicago, Illinois, USA. It was founded by the American Baptist Education Society with a donation from oil magnate and philanthropist John D. Rockefeller and incorporated in 1890...
in 1958, for which Jensen was awarded the Lasker Award
Lasker Award
The Lasker Awards have been awarded annually since 1946 to living persons who have made major contributions to medical science or who have performed public service on behalf of medicine. They are administered by the Lasker Foundation, founded by advertising pioneer Albert Lasker and his wife Mary...
. The gene for a second estrogen receptor (ERβ) was identified in 1996 by Kuiper et al. in rat prostate and ovary using degenerate ERalpha primers.