Raloxifene and Related Topics

Tamoxifen

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Selective estrogen receptor modulator used to prevent breast cancer in women and treat breast cancer in women and men.

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

In 2006, the large STAR clinical study concluded that raloxifene is also effective in reducing the incidence of breast cancer.

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

Estrogen receptor

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Estrogen receptors (ERs) are a group of proteins found inside cells.

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

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

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

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

Selective estrogen receptor modulator

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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).

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

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.

Raloxifene is used for prevention and treatment of postmenopausal osteoporosis and breast cancer prevention in high-risk postmenopausal women with osteoporosis.

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.

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.

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)

The medications tamoxifen or raloxifene may be used in an effort to prevent breast cancer in those who are at high risk of developing it.

Estrogen receptor alpha

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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)

Endometrial cancer

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Cancer that arises from the endometrium .

The autosomal dominant inheritance pattern seen in Lynch syndrome

Immunohistochemistry of endometrial endometrioid carcinoma with wild-type pattern of p53 expression, with variable proportion of tumor cell nuclei staining with variable intensity.

Vaginal ultrasonography with an endometrial fluid accumulation (darker area) in a postmenopausal uterus, a finding that is highly suspicious for endometrial cancer

Relative incidences of endometrial carcinomas by histopathology.

Endometrioid endometrial adenocarcinoma—very high magnification—H&E stain

A keyhole hysterectomy, one possible surgery to treat endometrial cancer

alt=A diagram of stage IA and IB endometrial cancer|Stage IA and IB endometrial cancer

alt=A diagram of stage II endometrial cancer|Stage II endometrial cancer

alt=A diagram of stage III endometrial cancer|Stage III endometrial cancer

alt=A diagram of stage IV endometrial cancer|Stage IV endometrial cancer

Raloxifene, a similar drug, did not raise the risk of endometrial cancer.

Clomifene

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

It has been found to be useful in the treatment of some cases of gynecomastia but it is not as effective as tamoxifen or raloxifene for this indication.