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estrogen receptors

Estrogen receptors (ERs) are located in the nucleus of estrogen-sensitive tissues (breast, endometrium, brain, bone, liver, heart). When the steroid hormone estrogen enters the nucleus of receptive tissues, it forms complexes with estrogen receptors, which then bind to estrogen response elements of DNA, activating expression of genes via stimulation of co-activators. The effects of estrogen stimulation vary from one tissue to another (pleiotropy).

anti-estrogenic drugs : cancers : co-activators, co-regulators, co-repressors : ERs : pleiotropy : raloxifene : selective estrogen receptor modulators : SERMs : Tamoxifen :

Two subtypes of estrogen receptors, ERα and ERβ, are known to mediate estrogen signaling through their function as ligand-dependent transcription factors [4]. After crossing the cellular membrane, estrogens bind to receptors ERα and ERβ, leading to receptor activation.

ERs interact with cis-regulatory elements of target genes:
a) by direct binding to conserved estrogen response elements (EREs; 5'-GGTCANNNTGACC-3', where N is any nucleotide), or
b) indirectly through association with AP1 or Sp1 transcription factor complexes and their respective binding sites [5-9].

Co-activators and co-repressors complex with estrogen receptors to regulate estrogen responses [10]. Cyclical turnover of transcriptional complexes and estrogen receptors at the regulatory elements of target genes provides an additional regulatory mechanism [11-13].

Potential mechanisms for the observed pleiotropic effects of estrogens include tissue-specific distribution of co-regulators, associated transcription factors complexes, and receptor subtypes and splice variants [14]. The consequence of ER activation appears to be alterations in transcriptional activity and expression profiles of target genes. Several genes, including those for trefoil factor 1/pS2, cathepsin D, cyclin D1, c-Myc and progesterone receptor, are positively regulated by ERα [15-20].[fft-s]

Because estrogen can stimulate cellular proliferation in tissues with estrogen-receptors, it is associated with increased risk of breast and endometrial carcinomas in replicating cells. Anti-estrogen chemotherapeutic agents compete with estrogen for binding to estrogen receptors, blocking estrogen activation of oncogenes. Selective estrogen receptor modulators, or SERMs, are a class of anti-estrogen drugs that selectively stimulate or inhibit the estrogen receptors of different target tissues.

Tamoxifen was the first SERM employed as an adjuvant treatment of estrogen receptor-positive breast cancers. It exerts an antiestrogenic effect by binding to the estrogen receptors of breast cells, preventing binding to coactivators and thus preventing activation of cell proliferation oncogenes. Because Tamoxifen stimulates endometrial estrogen receptors, increasing the risk of endometrial carcinoma, its use is restricted to treatment and it is not employed for prophylaxis of breast cancers. Another SERM, raloxifene is used to prevent osteoporosis and has demonstrated effectiveness against breast cancer without the problematic endometrial stimulation of Tamoxifen.

anti-estrogenic drugs : cancers : co-activators, co-regulators, co-repressors : ERs : pleiotropy : raloxifene : selective estrogen receptor modulators : SERMs : Tamoxifen :


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