27-Hydroxycholesterol Is an Endogenous Selective Estrogen Receptor Modulator

Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Molecular Endocrinology (Impact Factor: 4.02). 02/2008; 22(1):65-77. DOI: 10.1210/me.2007-0383
Source: PubMed


Selective estrogen receptor (ER) modulators (SERMs) are ER ligands whose relative agonist/antagonist activities vary in a cell- and promoter-dependent manner. The molecular basis underlying this selectivity can be attributed to the ability of these ligands to induce distinct alterations in ER structure leading to differential recruitment of coactivators and corepressors. Whether SERM activity is restricted to synthetic ligands or whether molecules exist in vivo that function in an analogous manner remains unresolved. However, the recent observation that oxysterols bind ER and antagonize the actions of 17beta-estradiol (E2) on the vascular wall suggests that this class of ligands may possess SERM activity. We demonstrate here that 27-hydroxycholesterol (27HC), the most prevalent oxysterol in circulation, functions as a SERM, the efficacy of which varies when assessed on different endpoints. Importantly, 27HC positively regulates both gene transcription and cell proliferation in cellular models of breast cancer. Using combinatorial peptide phage display, we have determined that 27HC induces a unique conformational change in both ERalpha and ERbeta, distinguishing it from E2 and other SERMs. Thus, as with other ER ligands, it appears that the unique pharmacological activity of 27HC relates to its ability to impact ER structure and modulate cofactor recruitment. Cumulatively, these data indicate that 27HC is an endogenous SERM with partial agonist activity in breast cancer cells and suggest that it may influence the pathology of breast cancer. Moreover, given the product-precursor relationship between 27HC and cholesterol, our findings have implications with respect to breast cancer risk in obese/hypercholesteremic individuals.

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Available from: Michihisa Umetani, Jul 08, 2014
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    • "Moreover, increasing 27-OHC levels repressed carotid artery re-endothelialization. Also cell type-specific pro-estrogenic actions of 27-OHC were reported [67,68], indicating that this oxysterol acts as an endogenous selective estrogen receptor modulator (SERM). Through its actions on both estrogen receptors and liver X receptors, 27-OHC decreases osteoblast differentiation and enhances osteoclastogenesis, resulting in increased bone resorbtion in mice [69,70]. "
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    ABSTRACT: Oxysterols are oxidized 27-carbon cholesterol derivatives or by-products of cholesterol biosynthesis, with a spectrum of biologic activities. Several oxysterols have cytotoxic and pro-apoptotic activities, the ability to interfere with the lateral domain organization, and packing of membrane lipids. These properties may account for their suggested roles in the pathology of diseases such as atherosclerosis, age-onset macular degeneration and Alzheimer's disease. Oxysterols also have the capacity to induce inflammatory responses and play roles in cell differentiation processes. The functions of oxysterols as intermediates in the synthesis of bile acids and steroid hormones, and as readily transportable forms of sterol, are well established. Furthermore, their actions as endogenous regulators of gene expression in lipid metabolism via liver X receptors and the Insig (insulin-induced gene) proteins have been investigated in detail. The cytoplasmic oxysterol-binding protein (OSBP) homologues form a group of oxysterol/cholesterol sensors that has recently attracted a lot of attention. However, their mode of action is, as yet, poorly understood. Retinoic acid receptor-related orphan receptors (ROR) α and γ, and Epstein-Barr virus induced gene 2 (EBI2) have been identified as novel oxysterol receptors, revealing new physiologic oxysterol effector mechanisms in development, metabolism, and immunity, and evoking enhanced interest in these compounds in the field of biomedicine.
    12/2012; 2(1). DOI:10.3390/biom2010076
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    • "However, of more relevance to humans was the discovery by Umetani et al. that the oxysterol, 27-hydroxycholesterol (27HC), can bind to and modulate the activity of ERα and ERβ both in vitro and in vivo [76] [77]. In mouse models of the cardiovascular system, 27HC behaves as an ER antagonist, and reduces the protective effects of 17-β estradiol [77], while in cellular models of ER positive breast cancer, 27HC behaves as an ER partial agonist [76]. More recently, we have demonstrated that 27HC has a detrimental effect on bone physiology; an activity that relates in part to its ability to disrupt ER action (discussed below) [78]. "
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    ABSTRACT: Estrogen Therapy and Hormone Therapy are effective options for the prevention and treatment of osteoporosis, although because of their significant side effect profile, long term use for these applications is not recommended. Whereas SERMs (Selective Estrogen Receptor Modulators) exhibit a more favorable side effect profile, the currently available medicines in this class are substantially less effective in bone than classical estrogens. However, the results of substantial efforts that have gone into defining the mechanisms that underlie the pharmacology of estrogens, antiestrogens and SERMs have informed the development of the next generation of SERMs and have led to the development of TSECs (Tissue Selective Estrogen Complexes), a new class of ER-modulator. Further, the recent determination that the oxysterol 27-hydroxycholesterol functions as an endogenous SERM has highlighted an unexpected link between hypercholesterolemia and bone biology and must be considered in any discussions of ER-pharmacology. This review considers the most recent progress in our understanding of ER pharmacology and how this has and will be translated into new medicines for the treatment and prevention of osteoporosis.
    Bone 11/2012; 53(1). DOI:10.1016/j.bone.2012.11.011 · 3.97 Impact Factor
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    • "Also important for transcriptional activation of ERs and other nuclear receptors by steroids and endocrine disruptors is the binding of co-regulators to the ligand-receptor complex [47], [48], [49], [50], [51], [52], [53]. Thus, even a low affinity ligand such as 27-hydroxy-cholesterol can have transcriptional activity for the ER in the presence of the appropriate co-activator [44]. "
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    ABSTRACT: Bisphenol A [BPA] is a widely dispersed environmental chemical that is of much concern because the BPA monomer is a weak transcriptional activator of human estrogen receptor α [ERα] and ERβ in cell culture. A BPA metabolite, 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene [MBP], has transcriptional activity at nM concentrations, which is 1000-fold lower than the concentration for estrogenic activity of BPA, suggesting that MBP may be an environmental estrogen. To investigate the structural basis for the activity of MBP at nM concentrations and the lower activity of BPA for human ERα and ERβ, we constructed 3D models of human ERα and ERβ with MBP and BPA for comparison with estradiol in these ERs. These 3D models suggest that MBP, but not BPA, has key contacts with amino acids in human ERα and ERβ that are important in binding of estradiol by these receptors. Metabolism of BPA to MBP increases the spacing between two phenolic rings, resulting in contacts between MBP and ERα and ERβ that mimic those of estradiol with these ERs. Mutagenesis of residues on these ERs that contact the phenolic hydroxyls will provide a test for our 3D models. Other environmental chemicals containing two appropriately spaced phenolic rings and an aliphatic spacer instead of an estrogenic B and C ring also may bind to ERα or ERβ and interfere with normal estrogen physiology. This analysis also may be useful in designing novel chemicals for regulating the actions of human ERα and ERβ.
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