A report on Estrogen receptor and Selective estrogen receptor modulator

A dimer of the ligand-binding region of ERβ (PDB rendering based on ).

Tamoxifen, a nonsteroidal triphenylethylene antiestrogen and a widely used drug in the treatment of breast cancer.

The domain structures of ERα and ERβ, including some of the known phosphorylation sites involved in ligand-independent regulation.

Figure 2: Nolvadex (tamoxifen) 20-milligram tablets (UK)

A dimer of the ligand-binding region of ERα (PDB rendering based on ).

Figure 3: The domain structures of ERα and ERβ, including some of the known phosphorylation sites involved in ligand-independent regulation.

Figure 4: Structural basis for the mechanism of estrogen receptor agonist and antagonist action. The structures shown here are of the ligand binding domain (LBD) of the estrogen receptor (green cartoon diagram) complexed with either the agonist diethylstilbestrol (top, ) or antagonist 4-hydroxytamoxifen (bottom, ). The ligands are depicted as space filling spheres (white = carbon, red = oxygen). When an agonist is bound to a nuclear receptor, the C-terminal alpha helix of the LBD (H12; light blue) is positioned such that a coactivator protein (red) can bind to the surface of the LBD. Shown here is just a small part of the coactivator protein, the so-called NR box containing the LXXLL amino acid sequence motif. Antagonists occupy the same ligand binding cavity of the nuclear receptor. However antagonist ligands in addition have a sidechain extension which sterically displaces H12 to occupy roughly the same position in space as coactivators bind. Hence coactivator binding to the LBD is blocked.

Figure 5: 4-hydroxytamoxifen (red) overlaid with 17β-estradiol (black)

Figure 6: Trans-form of clomifene with the triphenylethylene structure in red.

Figure 8: Chemical structure of toremifene

Figure 9: Raloxifene has a benzothiophene group (red) and is connected with a flexible carbonyl hinge to a phenyl 4-piperidinoethoxy side chain (green).

Figure 10: Chemical structure of nafoxidine with the dihydronapthalene group in red.

Figure 11: Chemical structure of lasofoxifene shows cis-oriented phenyls.

Figure 12: Bazedoxifene includes an indole system (red) which is connected to an amine through a benzyloxyethyl chain (green).

Figure 13: Chemical structure of ospemifene. Ethoxy side chain ends with a hydroxy group (red) instead of a dimethylamino group as with first-generation SERMs.

Figure 14: The ABCD steroid ring system in 17β-estradiol.

Figure 15: "A ring" (A) and "D ring" (D) marked in raloxifene.

Selective estrogen receptor modulators (SERMs), also known as estrogen receptor agonist/antagonists (ERAAs), are a class of drugs that act on the estrogen receptor (ER).

- Selective estrogen receptor modulator

Selective estrogen receptor modulators (e.g., tamoxifen, clomifene, raloxifene)

- Estrogen receptor

11 related topics with Alpha

Tamoxifen

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Crystallographic structure of afimoxifene (carbon = white, oxygen = red, nitrogen = blue) complexed with ligand binding domain of estrogen receptor alpha (ERα) (cyan ribbon).

Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and treat breast cancer in women and men.

Tamoxifen is used for the treatment of both early and advanced estrogen receptor-positive (ER-positive or ER+) breast cancer in pre- and postmenopausal women.

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 that is activated by the sex hormone estrogen.

Selective estrogen receptor modulators (e.g., tamoxifen, clomifene, raloxifene)

Raloxifene

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Medication used to prevent and treat osteoporosis in postmenopausal women and those on glucocorticoids.

Raloxifene is a selective estrogen receptor modulator (SERM) and therefore a mixed agonist–antagonist of the estrogen receptor (ER).

Antiestrogen

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Antiestrogens, also known as estrogen antagonists or estrogen blockers, are a class of drugs which prevent estrogens like estradiol from mediating their biological effects in the body.

They act by blocking the estrogen receptor (ER) and/or inhibiting or suppressing estrogen production.

Antiestrogens include selective estrogen receptor modulators (SERMs) like tamoxifen, clomifene, and raloxifene, the ER silent antagonist and selective estrogen receptor degrader (SERD) fulvestrant, aromatase inhibitors (AIs) like anastrozole, and antigonadotropins including androgens/anabolic steroids, progestogens, and GnRH analogues.

Clomifene

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Medication used to treat infertility in women who do not ovulate, including those with polycystic ovary syndrome.

Clomifene is in the selective estrogen receptor modulator (SERM) family of medication and is a nonsteroidal medication.

It is a mixed agonist and antagonist of the estrogen receptor (ER).

Estrogen receptor beta

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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.

Selective estrogen receptor modulators (e.g., tamoxifen, raloxifene)

Ethamoxytriphetol

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Synthetic nonsteroidal antiestrogen that was studied clinically in the late 1950s and early 1960s but was never marketed.

However, some estrogenic effects in the uterus have been observed, so it is not a pure antiestrogen (that is, a silent antagonist of the estrogen receptor (ER)) but is, instead, technically a selective estrogen receptor modulator (SERM).

Diethylstilbestrol

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Nonsteroidal estrogen medication, which is presently rarely used.

Testosterone levels with no treatment and with various estrogens in men with prostate cancer. Determinations were made with an early radioimmunoassay (RIA). Source was Shearer et al. (1973).

Testosterone levels with placebo and 0.2 to 5 mg/day diethylstilbestrol (DES) for 6 months in men with prostate cancer. Determinations were made with a radioimmunoassay (RIA). Source was Kent et al. (1973).

Chemical structures of estradiol and DES. Note the preservation of the two hydroxyl groups in DES and the similar distance between them relative to estradiol, which is notable when it is considered that DES was discovered serendipitously.

DES is an estrogen, or an agonist of the estrogen receptors, the biological target of estrogens like estradiol.

DES was the hormonal treatment of choice for advanced breast cancer in postmenopausal women until 1977, when the FDA approved tamoxifen, a selective estrogen receptor modulator with efficacy similar to DES but fewer side effects.

Breast cancer

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Cancer that develops from breast tissue.

Breast cancer showing an inverted nipple, lump, and skin dimpling

Tumor in the breast visualized by Breast-Computertomography (Breast-CT)

All types of alcoholic beverages, including beer, wine, or liquor, cause breast cancer.

Ducts and lobules, the main locations of breast cancers

Overview of signal transduction pathways involved in programmed cell death. Mutations leading to loss of this ability can lead to cancer formation.

Histopathologic types of breast cancer, with relative incidences and prognoses

A mobile breast cancer screening unit in New Zealand

Breasts after double mastectomy followed by nipple-sparing reconstruction with implants

An extreme example of an advanced recurrent breast cancer with an ulcerating axillary mass

Radical mastectomy, Halsted's surgical papers

The pink ribbon is a symbol to show support for breast cancer awareness.

Excised human breast tissue, showing an irregular, dense, white stellate area of cancer 2cm in diameter, within yellow fatty tissue

High-grade invasive ductal carcinoma, with minimal tubule formation, marked pleomorphism, and prominent mitoses, 40x field

Micrograph showing a lymph node invaded by ductal breast carcinoma, with an extension of the tumor beyond the lymph node

Neuropilin-2 expression in normal breast and breast carcinoma tissue

F-18 FDG PET/CT: A breast cancer metastasis to the right scapula

Elastography shows stiff cancer tissue on ultrasound imaging.

Ultrasound image shows irregularly shaped mass of breast cancer.

Infiltrating (invasive) breast carcinoma

Mammograms showing a normal breast (left) and a breast with cancer (right)

Additionally, G-protein coupled estrogen receptors have been associated with various cancers of the female reproductive system including breast cancer.

The selective estrogen receptor modulators reduce the risk of breast cancer but increase the risk of thromboembolism and endometrial cancer.

Nuclear receptor

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In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, cholesterol, and vitamins.

Structures of selected endogenous nuclear receptor ligands and the name of the receptor that each binds to.

Mechanism of class I nuclear receptor action. A class I nuclear receptor (NR), in the absence of ligand, is located in the cytosol. Hormone binding to the NR triggers dissociation of heat shock proteins (HSP), dimerization, and translocation to the nucleus, where the NR binds to a specific sequence of DNA known as a hormone response element (HRE). The nuclear receptor DNA complex in turn recruits other proteins that are responsible for transcription of downstream DNA into mRNA, which is eventually translated into protein, which results in a change in cell function.

Mechanism of class II nuclear receptor action. A class II nuclear receptor (NR), regardless of ligand-binding status, is located in the nucleus bound to DNA. For the purpose of illustration, the nuclear receptor shown here is the thyroid hormone receptor (TR) heterodimerized to the RXR. In the absence of ligand, the TR is bound to corepressor protein. Ligand binding to TR causes a dissociation of corepressor and recruitment of coactivator protein, which, in turn, recruits additional proteins such as RNA polymerase that are responsible for transcription of downstream DNA into RNA and eventually protein.

Structural basis for the mechanism of nuclear receptor agonist and antagonist action. The structures shown here are of the ligand binding domain (LBD) of the estrogen receptor (green cartoon diagram) complexed with either the agonist diethylstilbestrol (top, ) or antagonist 4-hydroxytamoxifen (bottom, ). The ligands are depicted as space filling spheres (white = carbon, red = oxygen). When an agonist is bound to a nuclear receptor, the C-terminal alpha helix of the LDB (H12; light blue) is positioned such that a coactivator protein (red) can bind to the surface of the LBD. Shown here is just a small part of the coactivator protein, the so-called NR box containing the LXXLL amino acid sequence motif. Antagonists occupy the same ligand binding cavity of the nuclear receptor. However antagonist ligands in addition have a sidechain extension which sterically displaces H12 to occupy roughly the same position in space as coactivators bind. Hence coactivator binding to the LBD is blocked.

Phylogenetic tree of human nuclear receptors

Type I nuclear receptors include members of subfamily 3, such as the androgen receptor, estrogen receptors, glucocorticoid receptor, and progesterone receptor.

Examples include Selective Androgen Receptor Modulators (SARMs), Selective Estrogen Receptor Modulators (SERMs) and Selective Progesterone Receptor Modulators (SPRMs).