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27-Hydroxycholesterol: a potential endogenous regulator of estrogen receptor signaling

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The selective estrogen receptor modulators (SERMs) are synthetic pharmaceuticals, the relative agonist and antagonist activities of which are not equivalent in all cells. Their discovery has raised the possibility that endogenous small molecules might exist that have similar properties and could have important physiological roles. In support of this hypothesis is the recent demonstration that the oxysterol 27-hydroxycholesterol (27HC) interacts with and modulates the transcriptional activity of both estrogen receptor (ER) subtypes and that the relative agonist and antagonist activity of 27HC is influenced by both cell and promoter context. Although there is limited information available on the role of 27HC in classical estrogen-responsive tissues, that which is available in animal models of cardiovascular disease and cellular models of breast cancer support a role for this ligand in ER signaling. These results provide an interesting potential link between cholesterol (and cholesterol metabolism) and ER function, the physiological and pathological importance of which remains to be determined.

Introduction

The pathologies associated with long-term estrogen deprivation, such as those that occur upon cessation of ovarian function at menopause or after surgical oophorectomy, highlight the important roles of estrogens in reproduction, maintenance of the skeleton and the central nervous and cardiovascular systems [1]. The increased incidence of climacteric symptoms, the onset of vasomotor instability and the increased risk of cardiovascular disease and osteoporosis observed in menopausal women have been attributed directly to decreased ovarian estradiol production [2]. Until recently, these pathologies have been treated using estrogen therapy (ET) with or without a concomitant progestin (hormone therapy; HT). It is now possible to achieve some of the benefits of ET/HT using selective estrogen receptor modulators (SERMs), the relative agonist and antagonist activities of which permit the treatment of conditions associated with estrogen deprivation but avoid various liabilities associated with standard interventions. The mechanisms underlying the protective actions of estrogens and SERMs in different tissues are slowly being unraveled, but a key observation made thus far is that different ligands acting through the same receptor have different biological activities in different cells. This realization has reinvigorated interest in the estrogen receptor (ER) as a therapeutic target and fueled the search for endogenous ligands that exhibit SERM-like activities.

Most, if not all, of the biological actions of estrogens are mediated by the intracellular ER expressed within target cells. A member of the nuclear receptor (NR) superfamily of ligand-inducible transcription factors, ER is expressed as two genetic isoforms, ERα and ERβ, which exhibit distinct and overlapping expression patterns and functions but share a common mechanism of action 3, 4, 5. On the whole, ERα is more widely expressed than ERβ, but in some tissues, such as the ovary, lung and prostate, ERβ is the predominant isoform [6]. In the absence of hormone, ER exists in an inactive state associated with a large inhibitory heat-shock-protein complex. Upon agonist binding, ER undergoes a conformational change that results in displacement of the associated heat-shock proteins and spontaneous homo- or hetero-dimerization between ERα and ERβ. Dimeric ER then interacts with the regulatory regions of target genes either directly through specific estrogen response elements (EREs) or indirectly through a physical interaction with other transcription factors (e.g. Sp1, nuclear factor-κB and AP1) already associated with the promoter [7]. Regardless, DNA-associated ER serves as the nucleation center for complexes comprising NR coactivators and components of the general transcription machinery. Antagonist binding to ER (or, in some cases, apo-ER) facilitates the recruitment of corepressors [i.e. nuclear hormone receptor corepressor (NCoR) and silencing mediator for retinoic acid receptor and thyroid-hormone receptor (SMRT)], which modify chromatin structure to repress target gene transcription. SERMs, such as tamoxifen and raloxifene, can be distinguished from classical antagonists, and from each other, by their effect on receptor conformation and the impact this has on differential engagement of coactivators and corepressors (Box 1). It is now well established that the overall conformation of ER is influenced by the nature of the bound ligand and that this translates into different pharmacological activities secondary to differential cofactor (coactivator or corepressor) recruitment [8]. (Figure 1)

In addition to regulating transcription, there is accumulating evidence that cytoplasmic ER engages in crosstalk with growth-factor signaling pathways through interactions with the adaptor protein Shc, the c-Src protein kinase complex, the regulatory subunit of phosphoinositide-3 kinase (p85) and caveolins [9]. How, and if, these interactions observed in vitro impact the physiological actions of estrogens or the pharmacological actions of SERMs remains to be determined.

Section snippets

An endogenous molecule with SERM characteristics

The apparent plasticity in ER structure and its impact on transcriptional activity has raised the question as to whether there exist endogenous molecules with SERM-like activities. Recently, it was determined that the oxysterol 27-hydroxycholesterol (27HC) can interact with and modulate the activity of ER both in vitro and in vivo 10, 11. Furthermore, the overall structure of the ER–27HC complex is distinct from apo-ER or estradiol-bound ER, a property shared by SERMs [10]. Although the degree

The ER-dependent actions of 27HC in the cardiovascular system

27HC is in a unique position to directly impact ER function in the cardiovascular system because it is the most prevalent circulating oxysterol, is particularly abundant within macrophages resident in atherosclerotic plaques and is produced in endothelial cells to regulate internal cholesterol stores. The levels of 27HC are ∼2 orders of magnitude higher in atheromas than in normal aorta, and this concentration rises as a function of lesion size [18]. It has already been established that

The ER-dependent actions of 27HC in the breast

27HC is a partial ER agonist in established cellular models of breast cancer, although in vivo confirmation of the importance of this activity is necessary [10]. 27HC recruits ERα to target gene promoters and controls transcription of ER target genes in a manner similar to estradiol [10]. Of more physiological importance is the demonstrated ability of 27HC to increase the proliferative capacity of ERα-positive breast-cancer cells. Despite a great deal of success in treating breast cancer with

Other potential roles of 27HC in ER biology

ER signaling is an important regulator of the development and maintenance of reproductive function in both sexes. Thus, it would be predicted that changes in 27HC would effect some, if not all, aspects of reproductive function. Interestingly, no reproductive abnormalities were observed in mouse models displaying different levels of 27HC [11]. Subtle defects might exist or perhaps are only manifest under restricted circumstances – possibilities that remain to be explored. The lack of an

Final Considerations

Although the in vivo studies of the cardiovascular system showed regulation of both genomic and nongenomic ER actions by 27HC, the in vitro studies focused exclusively on nuclear ER actions. Future in vitro studies should define how 27HC impacts the rapid aspects of ER signaling and how this might differ in a tissue-specific manner. Furthermore, it is clear that there is an immediate need for additional in vivo studies to address the specific functions of 27HC in ER-responsive tissues outside

Acknowledgements

We thank the members of the McDonnell laboratory for comments on this manuscript. This work was supported by the Department of Defense Breast Cancer Program (http://cdmrp.army.mil/bcrp) Predoctoral Traineeship Award W81XWH-06–1-0515 (C.D.D.) and National Institutes of Health (http://www.nih.gov) Grant 5R37DK048807 (D.P.M.).

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