Antiestrogens nuclear-receptors

X-ray structural determination of the LBDs of nuclear receptors bound to agonist or antagonist ligands has been a great step forward in understanding the mechanisms of action of receptors on a molecular level. For examples with estrogens and antiestrogens, see Refs [10-13]. 

Fig. 6.2. Proposed mechanisms of action of pure antiestrogens (fulvestrant). 1 Fulvestrant (ICI) binds to estrogen receptor (ER). 2 Fulvestrant binding to ER accelerates receptor degradation ( ER down-regulator ). 3 Rate of dimerization and nuclear localization of fulvestrant-ER complex is reduced. 4 Reduced binding of fulvestrant-ER to ERE. 5 No transcription of estrogen-responsive genes since AF-1 and AF-2 are inactive, no coactivators are recruited and the activity of RNA polymerase II is not activated (or inhibited) (Wakeling 2000)...

FULVESTRANT Eulvestrant (faslodex) is the first FDA-approved agent in the new class of ER downregulators. Eulvestrant is approved for postmenopausal women with ER-positive metastatic breast cancer that has progressed despite antiestrogen therapy. Fulvestrant binds to the ER with an affinity >100 times that of tamoxifen its long, bulky side-chain at the 7a position stericaUy hinders receptor dimerization, leading to increased ER turnover and disruption of nuclear localization. Unlike tamoxifen, which stabilizes or even increases ER expression, fulvestrant reduces the number of ER molecules in cells. 

Ruegg J, Swedenborg E, Wahlstrom D, Escande A, Balaguer P, Pettersson K, Pongratz I (2008) The transcription factor aryl hydrocarbon receptor nuclear translocator functions as an estrogen receptor beta-selective coactivator, and its recruitment to alternative pathways mediates antiestrogenic effects of dioxin. Mol Endocrinol 22 304—316... 

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