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). A characteristic that distinguishes these substances from pure ER agonists and antagonists is that their action is different in various tissues,thereby granting the possibility to selectively inhibit or stimulate estrogen-like action in various tissues.
Tamoxifen,sold under the brand name Nolvadex among others,is a selective estrogen receptor modulator used to prevent breast cancer in women and men. It is also being studied for other types of cancer. It has been used for Albright syndrome. Tamoxifen is typically taken daily by mouth for five years for breast cancer.
Estrogen receptors (ERs) are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen (17β-estradiol). Two classes of ER exist:nuclear estrogen receptors,which are members of the nuclear receptor family of intracellular receptors,and membrane estrogen receptors (mERs),which are mostly G protein-coupled receptors. This article refers to the former (ER).
Proline-,glutamic acid- and leucine-rich protein 1 (PELP1) also known as modulator of non-genomic activity of estrogen receptor (MNAR) and transcription factor HMX3 is a protein that in humans is encoded by the PELP1 gene. is a transcriptional corepressor for nuclear receptors such as glucocorticoid receptors and a coactivator for estrogen receptors.
Virgil Craig Jordan,,is a scientist with American and British citizenship specializing in drugs for breast cancer treatment and prevention. Currently,he is Professor of Breast Medical Oncology,and Professor of Molecular and Cellular Oncology at the University of Texas MD Anderson Cancer Center,Houston,Texas. Previously,he was Scientific Director and Vice Chairman of Oncology at the Lombardi Comprehensive Cancer Center of Georgetown University. Jordan was the first to discover the breast cancer prevention properties of tamoxifen and the scientific principles for adjuvant therapy with antihormones. More recently his work has branched out into the prevention of multiple diseases in women with the discovery of the drug group,selective estrogen receptor modulator (SERMs). Currently,he plans to develop a new Hormone Replacement Therapy (HRT) for post-menopausal women that prevents breast cancer and does not increase the risk of breast cancer.
Hormonal therapy in oncology is hormone therapy for cancer and is one of the major modalities of medical oncology,others being cytotoxic chemotherapy and targeted therapy (biotherapeutics). It involves the manipulation of the endocrine system through exogenous or external administration of specific hormones,particularly steroid hormones,or drugs which inhibit the production or activity of such hormones. Because steroid hormones are powerful drivers of gene expression in certain cancer cells,changing the levels or activity of certain hormones can cause certain cancers to cease growing,or even undergo cell death. Surgical removal of endocrine organs,such as orchiectomy and oophorectomy can also be employed as a form of hormonal therapy.
The nuclear receptor coactivator 3 also known as NCOA3 is a protein that,in humans,is encoded by the NCOA3 gene. NCOA3 is also frequently called 'amplified in breast 1' (AIB1),steroid receptor coactivator-3 (SRC-3),or thyroid hormone receptor activator molecule 1 (TRAM-1).
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 are one of three types of sex hormone antagonists,the others being antiandrogens and antiprogestogens. Antiestrogens are commonly used to stop steroid hormones,estrogen,from binding to the estrogen receptors leading to the decrease of estrogen levels. Decreased levels of estrogen can lead to complications in sexual development. Antiandrogens are sex hormone antagonists which are able to lower the production and the effects that testosterone can have on female bodies.
Breast cancer anti-estrogen resistance protein 3 is a protein that in humans is encoded by the BCAR3 gene.
Antineoplastic resistance,often used interchangeably with chemotherapy resistance,is the resistance of neoplastic (cancerous) cells,or the ability of cancer cells to survive and grow despite anti-cancer therapies. In some cases,cancers can evolve resistance to multiple drugs,called multiple drug resistance.
Triphenylethylene (TPE) is a simple aromatic hydrocarbon that possesses weak estrogenic activity. Its estrogenic effects were discovered in 1937. TPE was derived from structural modification of the more potent estrogen diethylstilbestrol,which is a member of the stilbestrol group of nonsteroidal estrogens.
Ethamoxytriphetol is a synthetic nonsteroidal antiestrogen that was studied clinically in the late 1950s and early 1960s but was never marketed. MER-25 was first reported in 1958,and was the first antiestrogen to be discovered. It has been described as "essentially devoid of estrogenic activity" and as having "very low estrogenic activity in all species tested". However,some estrogenic effects in the uterus have been observed,so it is not a pure antiestrogen but is,instead,technically a selective estrogen receptor modulator (SERM). For all intents and purposes,it is a nearly pure antiestrogen,however.
Estrogen deprivation therapy,also known as endocrine therapy,is a form of hormone therapy that is used in the treatment of breast cancer. Modalities include antiestrogens or estrogen blockers such as selective estrogen receptor modulators (SERMs) like tamoxifen,selective estrogen receptor degraders like fulvestrant,and aromatase inhibitors like anastrozole and ovariectomy.
Etacstil is an orally active,nonsteroidal,combined selective estrogen receptor modulator (SERM) and selective estrogen receptor degrader (SERD) that was developed for the treatment of estrogen receptor-positive breast cancer. It was shown to overcome antiestrogen resistance in breast cancer by altering the shape of the estrogen receptor,thus exhibiting SERD properties. Etacstil is a tamoxifen derivative and one of the first drugs to overcome tamoxifen-resistance. It is the predecessor of GW-7604,of which etacstil is a prodrug. This is analogous to the case of tamoxifen being a prodrug of afimoxifene (4-hydroxytamoxifen).
Endoxifen,also known as 4-hydroxy-N-desmethyltamoxifen,is a nonsteroidal selective estrogen receptor modulator (SERM) of the triphenylethylene group as well as a protein kinase C (PKC) inhibitor. It is under development for the treatment of estrogen receptor-positive breast cancer and for the treatment of mania in bipolar disorder. It is taken by mouth.
A hormone-sensitive cancer,or hormone-dependent cancer,is a type of cancer that is dependent on a hormone for growth and/or survival. Examples include breast cancer,which is dependent on estrogens like estradiol,and prostate cancer,which is dependent on androgens like testosterone.
John Albert Katzenellenbogen is an American Professor of Chemistry at the University of Illinois at Urbana-Champaign. He studies the development of novel agents for the treatment of hormone-responsive and non-responsive breast and prostate cancers and the design of estrogens and antiestrogens that have a favorable balance of beneficial versus detrimental effects.
Benita S. Katzenellenbogen née Schulman is an American physiologist and cell biologist at the University of Illinois at Urbana-Champaign. She has studied cancer,endocrinology,and women's health,focusing on nuclear receptors. She also dedicated efforts to focusing on improving the effectiveness of endocrine therapies in breast cancer.
ERX-11,also known as ERαcoregulator-binding modulator-11,is a novel antiestrogen and experimental hormonal antineoplastic agent which is being researched for the potential treatment of estrogen receptor-positive breast cancer. It is not a competitive antagonist of the estrogen receptor (ER) like conventional antiestrogens such as tamoxifen or fulvestrant;instead of binding to the ligand-binding site of the ER,ERX-11 interacts with a different part of the ERαand blocks protein–protein interactions of the ERαwith coregulators that are necessary for the receptor to act and regulate gene expression. It was designed to bind to the coregulator binding region of the ERαand inhibit the ERα/coactivator interaction,although its precise binding site and mode of action have yet to be fully elucidated and understood. Nonetheless,it is clear that ERX-11 binds within the AF-2 domain of the ERα.
Endocrine therapy is a common treatment for estrogen receptor positive breast cancer. However,resistance to this therapy can develop,leading to relapse and progression of disease. This highlights the need for new strategies to combat this resistance.
