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Review
. 2010 Dec;10(6):629-36.
doi: 10.1016/j.coph.2010.09.009. Epub 2010 Oct 14.

Regulation of specific target genes and biological responses by estrogen receptor subtype agonists

Dale C Leitman  1 , Sreenivasan Paruthiyil, Omar I Vivar, Elise F Saunier, Candice B Herber, Isaac Cohen, Mary Tagliaferri, Terence P Speed
Affiliations
Review

Regulation of specific target genes and biological responses by estrogen receptor subtype agonists

Dale C Leitman et al. Curr Opin Pharmacol. 2010 Dec.

Abstract

Estrogenic effects are mediated through two estrogen receptor (ER) subtypes, ERα and ERβ. Estrogens are the most commonly prescribed drugs to treat menopausal conditions, but by non-selectively triggering both ERα and ERβ pathways in different tissues they can cause serious adverse effects. The different sizes of the binding pockets and sequences of their activation function domains indicate that ERα and ERβ should have different specificities for ligands and biological responses that can be exploited for designing safer and more selective estrogens. ERα and ERβ regulate different genes by binding to different regulatory elements and recruiting different transcription and chromatin remodeling factors that are expressed in a cell-specific manner. ERα-selective and ERβ-selective agonists have been identified that demonstrate that the two ERs produce distinct biological effects. ERα and ERβ agonists are a promising new approach for treating specific conditions associated with menopause.

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Figures

Figure 1
Figure 1
Comparison of the structures and homology between ERα and ERβ. Human ERα contains 595 amino acids whereas ERβ contains 530 amino acids. The DNA binding domains are nearly identical whereas the A/B domain and LBD, which contains AF-1 and AF-2, respectively, have the least homology.
Figure 2
Figure 2
Potential classes of estrogen receptor subtype agonists (ERSAs) for drug therapy. Potential ERβ-selective estrogens. (A) ERβ binders (ERB-041) are estrogens that are selective because they bind to ERβ with a much higher affinity than ERα. (B) ERβ activators (MF101, liquiritigenin) bind to ERα and ERβ with a similar affinity, but form a functional complex when bound to ERβ (left panel), but not ERα (right panel). An ERβ binder/activator (DPN) selectively binds to (A) and activates ERβ (B). Potential ERα-selective agonists. (C) ERα binders (PPT) bind to ERα with a much higher affinity than ERβ. (D) Tissue selective ERα agonists (Radix Glycyrrhiza and Radix Pueraria) form a functional transcription complex at response elements with ERα in some tissues (left panel), but not in other tissues (right panel). (E) A ligand such as E2 binds to both ERα subunits that leads to the recruitment of coregulators and transcription factors (left panel). In the presence of an ERα coagonist (chalcone) E2 binds to one subunit and the coagonist binds to the other subunit (right panel). The heteroliganded ERα could create a different conformation than the homoliganded ERα which leads to the recruitment of different coregulators and/or transcription factors.
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References

    1. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. Jama. 2002;288:321–333. This seminal study was the first randomized, placebo controlled study to evaluate the effects of hormone therapy on postmenopausal women. The study found that the risks of hormone therapy exceed the benefits.

    1. Shang Y. Molecular mechanisms of oestrogen and SERMs in endometrial carcinogenesis. Nat Rev Cancer. 2006;6:360–368. - PubMed
    1. Heldring N, Pike A, Andersson S, Matthews J, Cheng G, Hartman J, Tujague M, Strom A, Treuter E, Warner M, et al. Estrogen receptors: how do they signal and what are their targets. Physiol Rev. 2007;87:905–931. - PubMed
    1. Levin ER. Plasma membrane estrogen receptors. Trends Endocrinol Metab. 2009;20:477–482. - PMC - PubMed
    1. Stauffer SR, Coletta CJ, Tedesco R, Nishiguchi G, Carlson K, Sun J, Katzenellenbogen BS, Katzenellenbogen JA. Pyrazole ligands: structure-affinity/activity relationships and estrogen receptor-alpha-selective agonists. J Med Chem. 2000;43:4934–4947. - PubMed

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