Estrogen-related receptor α as a therapeutic target in cancer

in Endocrine-Related Cancer

The orphan receptor estrogen-related receptor α (ERRα) is a member of the nuclear receptor superfamily of ligand-regulated transcription factors. This protein is structurally most related to the canonical estrogen receptor and has been shown to modulate estrogen signaling in some contexts. These observations have heightened interest in ERRα as a therapeutic target in both breast and ovarian cancer and in other estrogenopathies. This review details our present understanding of ERRα action with a view to highlight specific aspects of its signal-transduction pathway in breast cancer that may be amenable to pharmaceutical manipulation.

Abstract

The orphan receptor estrogen-related receptor α (ERRα) is a member of the nuclear receptor superfamily of ligand-regulated transcription factors. This protein is structurally most related to the canonical estrogen receptor and has been shown to modulate estrogen signaling in some contexts. These observations have heightened interest in ERRα as a therapeutic target in both breast and ovarian cancer and in other estrogenopathies. This review details our present understanding of ERRα action with a view to highlight specific aspects of its signal-transduction pathway in breast cancer that may be amenable to pharmaceutical manipulation.

Introduction

Drugs that function by inhibiting ERα signaling have been and will continue to be an important part of pharmacotherapy in breast cancer. Foremost among these therapies are selective estrogen receptor modulators (SERMs), compounds which antagonize the mitogenic actions of estrogens in breast tissue but which function as estrogens in bone and the cardiovascular system. Of late, aromatase inhibitors have proven to be more efficacious than SERMs in certain circumstances. Although these two classes of drugs are extremely effective, it is clear that there remains a need for agents that target estrogen signaling by alternate mechanisms. Of significance in this regard is the observation that SERMs are clinically beneficial for only 50–80% of ERα-positive breast cancer patients. An additional limitation of anti-estrogen treatment is that many patients, particularly those with metastatic disease, rapidly develop resistance (Robertson et al. 1996). Indeed, in some cases it has been observed that tumors in which tamoxifen initially functions as an antagonist can ‘switch’ to recognizing this drug as an agonist. Not surprisingly, resistance to aromatase inhibitors has also emerged as a significant issue in the clinic. Resistance to anti-estrogens, SERMs, and aromatase inhibitors is multifactorial in cause, and an array of potential mechanisms to explain this phenomenon has emerged. Leading hypotheses include changes in drug metabolism, receptor mutations, inappropriate activation of growth and survival pathways, and alterations in the activity of the ERα-signaling pathway. These activities underscore the need for novel strategies to inhibit estrogen signaling in breast cancer. Our investigation into the estrogen-related receptors (ERRs) in breast cancer was prompted in part by the hypothesis that these orphan nuclear receptors may play a role in both de novo and acquired resistance to anti-hormonal agents. ERR expression, structure, and function suggest that these nuclear receptors may be intimately linked to estrogen signaling. This review will discuss the relationship between the ERRα pathway and classical estrogen signaling and evaluate the present evidence supporting a role for ERRα in breast cancer. Finally, we will identify key obstacles and questions that must be resolved if ERRα is to be utilized as a therapeutic target in breast cancer.

The estrogen receptor-signaling pathway

In the absence of hormone, estrogen receptor (ER) resides in either the cytoplasm or nucleus of the target cells associated with a large heatshock protein–chaperone complex that maintains the receptor in a transcriptionally inactive form. Upon binding a ligand, the receptor undergoes a conformational change leading to its displacement from the chaperone complex and subsequent dimerization. In this biochemical state, the receptor can interact with target gene promoters in a direct manner through specific estrogen-response elements (EREs) or indirectly through interactions with proteins associated with the promoter. The DNA-bound receptor then nucleates the assembly of a large multiprotein co-activator complex that serves to remodel local chromatin structure, stabilize the preinitiation complex and enhance transcriptional output. It is important to note that there are two genetically distinct ERs in target cells: ERα and ERβ. Additional complexity is introduced into the model described above as these receptor subtypes can form both homo- and heterodimeric complexes, each of which manifests distinct functional activities. Most of what we know about estrogen signaling in the breast comes from studies of ERα action. The specific roles of ERβ and the functional consequences of its expression in normal and malignant breast remain to be determined.

Until relatively recently, it was believed that estrogen binding was the only biochemical event that enabled the conversion of ER from an inactive to a transcriptionally active form in cells. However, several seminal studies published by the O’Malley group indicated that ER transcriptional activity can be activated in a ligand-independent manner by impinging signaling pathways. It is now clear that the transcriptional activity of ERα and other nuclear receptors can be altered by post-translational receptor modifications, the presence of non-hormone receptor ligands, and the particular complement of other nuclear receptors active at a given time. Since many cofactors (both co-activators and co-repressors) interact with multiple nuclear receptors and may be in limited supply, cofactor availability has also been suggested to play a role in determining the cell-specific activity of ERα (McKenna et al. 1999). The activity of ERα can also be regulated by changes in the phosphorylation state of the receptor downstream of growth factor stimulation. Increases in phosphorylation can enhance both ligand-independent and ligand-dependent activity in vitro (Kato et al. 1995). ERα phosphorylation has recently been implicated in tamoxifen resistance, which suggests new methods for predicting the occurrence of refractory tumors as well as for use in their treatment (Cui et al. 2006). Each of the signaling pathways impinging on ERα presents a potential avenue through which other nuclear receptors including the ERRs may influence ERα. More generally, the entire complicated web of ERα regulation introduces numerous opportunities for the pharmacologic regulation of its activity.

Overview of estrogen-related receptors

In 1988, Giguere et al.(1988) cloned the first orphan receptors, ERRα and ERRβ, using the DNA-binding domain (DBD) of ERα as a probe to screen recombinant DNA libraries. A third isoform, ERRγ, was later identified by Eudy et al.(1998). Sequence analysis reveals that the ERRs and the classical estrogen receptors share a high degree of homology within their DNA and ligand-binding domains (LBDs) (Laudet et al. 1992). In particular, ERRα shares with ERα approximately 68% sequence identity within the DBD and 33% within the LBD (Fig. 1). This relationship provides a structural basis both for the conserved nature of DNA binding and the divergence in hormone binding between these two receptors. Each characteristic has important consequences on the functional relationship between ERRα and ERα.

The finding that ERRα and ERα bind to similar DNA-response elements in target genes is not surprising in light of the observation that the P-box region of the DNA-binding domains (which determines DNA specificity) in both the ERs and ERRs is highly conserved (Laudet et al. 1992). DNA-binding studies performed in vitro indicate that ERα and ERRα may have slightly different DNA-binding preferences. While ERα binds preferentially to the sequence AGGTCAnnnTGACCT, termed an estrogen-response element (ERE), ERRα binds with the highest affinity to the extended half-site sequence TnAAGGTCA, termed an estrogen-related response element (ERRE; Sladek et al. 1997, Vanacker et al. 1999a,b). When initially discovered, this divergence in DNA-binding preference in vitro suggested that these receptors might not display significant DNA-binding cross-reactivity. However, recently, ERα has been found to activate many of its target genes through imperfect EREs composed of multiple half-sites. This supports the hypothesis that many EREs may function as ERREs in vivo, and conversely, that a subset of ERREs may function as EREs (Vanacker et al. 1999a,b).

The transcriptional activity of several endogenous genes is regulated by both ERRα and ERα, including the pS2 breast cancer marker, osteopontin and lactoferrin (Yang et al. 1996, Vanacker et al. 1999a,b, Lu et al. 2001, Kraus et al. 2002). Early evidence that ERRα can activate ERα target genes in the absence of estrogen suggested that the ERRs might drive estrogen-independent breast tumor growth. These findings not only generated considerable interest in elucidating the role of ERRα in the development and maintenance of tumors, but also raised the possibility that ERRα antagonists might be of benefit in treating breast cancer. As yet, this hypothesis has not been formally tested. However, it has been demonstrated that in some contexts, ERRα can repress ligand-activated ERα-dependent transcriptional activity. Given the similarity in the DNA-binding specificity of these two receptors, it is possible that direct competition for promoter occupancy can explain this inhibitory activity (Fig. 2). The hypothesis that ERα and ERRα compete for binding to a shared promoter is supported by gene-expression analysis performed on breast cancer samples. In particular, Suzuki et al.(2004) found that the correlation between the expression of ERα and ERα target genes that contain an ERE within their promoters is significantly blunted when there is coincident high levels of ERRα expression. In contrast, the correlation between ERα and genes thought to be regulated by ERα binding to a non-canonical ERE is not altered by ERRα expression. Importantly, gel shift assays performed by Krause et al. verified that ERα and ERRα can compete directly for promoter binding in MCF7 cells. They went on to show that this is not merely a passive process but that ERRα recruits co-repressor proteins that actively suppress the expression of ERα responsive target genes (Kraus et al. 2002). However, they note that the relationship between these two receptors seems to depend on the particular cell line tested. Furthermore, it has been shown that the phosphorylation state of ERRα can alter its activity. Of particular relevance, it has been shown that phosphorylation of ERRα, downstream of epidermal growth factor receptor (EGFR) signaling, increases its transcriptional activity on the pS2 promoter. However, this increased activity seems to be promoter selective as ERRα-mediated auto-induction is not enhanced (Yang et al. 1998, Barry & Giguere 2005). The publication of the data from chromatin immunoprecipitation (ChIP) on ChIP studies aimed at defining the primary target genes of ERRα (discussed only at meetings thus far) should provide the information needed to define the extent of overlap in genes regulated by these two receptors.

Indirect crosstalk between ERRα and ERα

It has recently been demonstrated that ERRα can stimulate the transcription of the aromatase gene, as well as the genes for several other key steroidogenic enzymes (Yang et al. 1998, Seely et al. 2005; Fig. 2). As local mammary steroidogenesis is a significant source of estrogen in post-menopausal women, induction of steroidogenic enzymes may be a clinically important mechanism of ERRα–ERα crosstalk (Simpson 2003). In post-menopausal women, ERRα-stimulated aromatase transcription in the breast may enhance local production of estrogen, which would in turn stimulate breast cancer progression. Beyond the local role of ERRα, recent data suggest that ERRα induces transcription of the steroid sulfotransferase SULT2A1 within the adrenal glands (Seely et al. 2005). This sulfotransferase maintains high levels of peripheral dehydroepiandrosterone sulfate (DHEAS), which in turn is thought to be required for estrogen synthesis in certain peripheral tissues. An additional role of SULT2A1, however, is the inactivation of the SERMs tamoxifen and raloxifene (Apak & Duffel 2004). Therefore, by activating SULT2A1, ERRα may both enhance estrogen production and decrease the efficacy of these SERMs. Further studies are warranted by the clinical significance of tamoxifen resistance as well as the evidence linking the ERRα and ERα signaling pathways.

Insights into ERRα–ERα crosstalk from studies in bone

Bone development and maintenance is an additional potential point of convergence between ERα and ERRα as these receptors are co-expressed in osteoblasts in vivo and in vitro (Bonnelye et al. 2002). The importance of ERα in bone is supported by the finding that the cessation of ovarian estrogen production in post-menopausal women is largely responsible for the development of osteoporosis. In this setting, circulating estrogen levels track with lumbar spine bone mineral density (LS-BMD) (Felson et al. 1993, Bonnelye & Aubin 2005). ERRα is expressed throughout osteoblast development, and in vitro bone nodule formation can be inhibited by knocking down ERRα expression (Bonnelye et al. 2001). Furthermore, a polymorphism has recently been discovered within the ERRα promoter that is associated with high LS-BMD (Laflamme et al. 2005). Patients with this allelic variant, in which a portion of the promoter containing an ERRE is amplified up to four times, express increased levels of ERRα protein. Given the potential regulation of steroidogenesis by ERRα discussed above, ERRα activity may serve to enhance ERα signaling, leading to improved bone maintenance. Alternately, it may serve to activate ERα target genes in bone in the absence of estrogen as indicated by the finding that the shared ERα and ERRα target lactoferrin promotes bone formation in vivo and protects osteoblasts from apoptosis in vitro (Yang et al. 1996, Cornish et al. 2004). ERRα also may afford protection from bone loss independent of ERα as it has been shown to directly regulate several genes that are associated with osteoblast function, such as osteopontin and c-erbA1 (Bonnelye & Aubin 2005). Although these findings indicate several possible levels of interplay between ERα and ERRα, their specific roles in physiology and pathology require further investigation.

The emerging role of ERRα in cancer

In recent years, two independent clinical studies have implicated ERRα in breast cancer progression (Ariazi et al. 2002, Suzuki et al. 2004). Analysis of 102 breast cancer samples revealed that the expression of ERRα in greater than 10% of malignant cells was associated with a 20% decrease in overall disease survival at 13 years (relative risk=5.1). Furthermore, ERRα was found to be an independent prognostic factor controlling for factors, including ERα status. Although in this study there was no correlation between ERRα and ERα expression, an earlier study by Ariazi et al. demonstrated that high levels of ERRα mRNA correlated with ERα-negative tumor status in the 38 tumors examined. Analysis of the other ERRs revealed that high expression of ERRγ correlates with positive outcomes for patients with breast cancer suggesting an opposing role to that of ERRα (Ariazi et al. 2002).

Following the studies implicating ERRα in breast cancer, the expression and activity of this orphan nuclear receptor have been measured in ovarian, prostate, and colorectal cancer. Sun et al.(2005) demonstrated that approximately 60% of ovarian malignancies express ERRα and postulated that ERRα may play an important role by modulating ERα signaling in this context. Measuring the expression of the ERRs in 33 ovarian cancer samples and 12 samples from normal ovaries, they demonstrated that a greater number of cancer samples had ERRα mRNA levels detectable by quantitative real-time PCR. Furthermore, a positive correlation between ERRα expression and advanced tumor stage and grade was observed. Notably, multivariate analysis implicated ERRα expression as an independent prognostic factor for poor overall patient survival. In contrast to the success of targeting ERα in breast cancer, this receptor has not been a useful target in ovarian cancer. In vitro data demonstrating the proliferative role of estrogen in ovarian cancer cell lines and the in vivo correlation between circulating estrogens and tumor development suggest that ERα likely plays an essential role in ovarian cancer. However, only 15–20% of patients with ERα-positive tumors show a clinical response to anti-estrogens (Clinton & Hua 1997). Given the potential crosstalk between the estrogen-signaling pathway and that of ERRα, it is tempting to speculate that ERRα may be part of the explanation for the common resistance of ovarian cancers to ERα blockade.

ERRα in energy homeostasis: a potential link to cancer?

From what is presently known about ERRα, it appears that it may have two distinct functional activities in the cell. ERRα was first described as a regulator offatty acid oxidation, mitochondrial biogenesis, and oxidative phosphorylation (Sladek et al. 1997). More recent literature, as reviewed herein, establishes a role for ERRα as a modulator of ER signaling (Giguere 2002). How, and if, these activities are linked in the pathogenesis of cancers expressing ERRα remains an open question.

In considering the potential for targeting the ERRα to alter estrogen signaling, it is worth noting the wide range of roles that it can play in physiological and pathological settings. The tissue distribution of ERRα in the mouse provided the first clue that ERRα may regulate metabolic activity. Almost all organs express ERRα at some level. However, it is most highly expressed in kidney, heart, cerebellum, intestine, and skeletal muscle, tissues that preferentially utilize fatty acids as energy sources (Bookout & Mangelsdorf 2006). The function of ERRα as a metabolic regulator is further supported by the observation that ERRα-null mice demonstrate impaired fat metabolism and absorption (Luo et al. 2003). That the expression of ERRα is elevated in exercising muscle and fasting liver specifically implicates this receptor in β-oxidation of fatty acids, which occurs under the same conditions. On a mechanistic level, several studies have revealed that ERRα is involved in the transcriptional regulation of genes required for mitochondrial biogenesis, oxidative phosphorylation, and fatty acid oxidation (Wu et al. 1999, Yoon et al. 2001, Huss et al. 2004, Mootha et al. 2004).

Most of the metabolic studies of ERRα focus on its role as the downstream effector of PPARγ co-activator 1α (PGC-1α). PGC-1α is a promiscuous nuclear receptor co-activator expressed at low basal levels but induced by fasting and other metabolic stresses (Puigserver & Spiegelman 2003). PGC-1β, a related cofactor, may have similar functions under certain circumstances, although its expression level is not as acutely regulated by variations in energy demand (Yoon et al. 2001, Lin et al. 2003, 2005). Rather than being regulated by ligand, the magnitude of ERRα activity is thought to be largely dependent on the presence of transcriptional co-activators, such as PGC-1α and PGC-1β. Interest in the ERR–PGC-1 regulatory axis was heightened by the observation that there is a decrease in both PGC-1α and PGC-1β in the skeletal muscle of patients with diabetes and obesity (Kelley et al. 2002, Mootha et al. 2003, Oberkofler et al. 2004, Lowell & Shulman 2005). The recently identified allelic variant of the ERRα promoter thought to sensitize ERRα to PGC-1α co-activation was found to be associated not only with high bone density, but also with obesity (Kamei et al. 2005). It is essential that the effects of ERRα activity in both energy metabolism and tumor biology be understood if we are to further develop ERRα as a therapeutic target.

Pharmacologic regulation of ERRα activity

As of yet, the ERRs have not been shown to interact with any physiologically relevant small molecules, leading to the suggestion that these receptors manifest constitutive activity (Xie et al. 1999, Chen et al. 2001, Greschik et al. 2002). Crystallographic analyses of both apo-ERRα and apo-ERRγ have indicated that these receptors are in a transcriptionally active conformation (Greschik et al. 2002, 2004, Kallen et al. 2004). Furthermore, the lack of any obvious electron density in the ligand-binding pockets (LBP) indicates that the apo-receptors are indeed capable of adopting an active conformation (Greschik et al. 2002, Kallen et al. 2004). With an estimated volume of only 100 Å, the LBP of ERRα is large enough to accommodate the binding of a small molecule agonist of only four or five carbons. It is not surprising, therefore, that the vast majority of pharmacologically active ERRα ligands act as antagonists.

The first compounds screened for activity on the ERRs were known endocrine disrupters with estrogen-like activity. Yang & Chen (1999) found that the organochlorine pesticides toxaphene and chlordane function as low-affinity ERRα antagonists in the micromolar range. The synthetic estrogen diethylstilbesterol was also found to act as a weak antagonist, disrupting co-activator–ERR interaction and inhibiting constitutive activity of all three ERRs in transfection assays (Coward et al. 2001, Tremblay et al. 2001). Recently, high throughput screening yielded an ERRα inverse agonist which was subsequently optimized to the ERRα-selective XCT790 (Busch et al. 2004). This thiadiazole-based compound inhibits ERRα activity in transfection assays with submicromolar activity, and has been used to further define the role of ERRα in the regulation of metabolic signaling pathways (Mootha et al. 2004, Willy et al. 2004). Several other ERRα inverse agonists with submicromolar activity have been reported, including an indole, pyrazole, and thiazolidinedione (Deuschle et al. 2004, Player et al. 2004, Nolte et al. 2005). Unfortunately, many of the antagonists reported cross-react with ERRβ and ERRγ as well as with a variety of other nuclear receptors. As an alternative to the small molecule approach, our lab has used phage display to develop several ERRα peptide antagonists. These peptides bind with high affinity to ERRα and block co-activator binding (S Gaillard & DP McDonnell, unpublished observations). In contrast to the numerous ERRα antagonists reported, few natural or synthetic agonists of ERRα have been identified. However, the phytoestrogens flavone and isoflavone function in transfection assays as non-selective ERR agonists (Suetsugi et al. 2003). Due to the small size of the LBP, it may be necessary to design drugs to enhance ERRα activity using alternative strategies, such as altering the phosphorylation status of the receptor or targeting other upstream regulators of ERRα.

Further development of ERRα as a therapeutic target

A clear understanding of ERRα activity is likely to shed light on unresolved aspects of ER signaling and pharmacology and may validate ERRα as a useful therapeutic target in breast cancer. Ultimately, if we are to pharmacologically manipulate ERRα in the setting of metabolic disorders or cancer, we must determine if ERRα expression and activity is a cause or consequence of the underlying pathology. Regarding the role of ERRα in breast cancer, larger clinical studies as well as investigation into the molecular mechanism of ERRα function in this particular setting are essential. The extent to which ERRα signaling is intertwined with that of ERα and the extent to which ERRα function in cancer is distinct from its activity as a metabolic regulator are as yet undetermined. Answers to these compelling questions will both inform and motivate future development of ERRα as a therapeutic target within the settings of malignancy and metabolic disorders.

Figure 1
Figure 1

Amino acid identity between the ERs and ERRs within the DNA-binding domain (DBD) and the ligand-binding domain (LBD). Although several alternative splice variants of the ERRs have been identified, the total number of amino acids in the most common variant is shown above (Adapted from Laudet 1997, reproduced with permission from the Society for Endocrinology).

Citation: Endocrine-Related Cancer Endocr Relat Cancer 13, Supplement_1; 10.1677/erc.1.01292

Figure 2
Figure 2

(A) ERα and ERRα bind to similar promoter elements. Potentially, ERRα could substitute for ERα on an ERE, or a heterodimer formation could occur. The relative affinity for promoter binding and the transcriptional activity of ERRα are each likely to partially be determined by the entire promoter context. (B) Many nuclear receptor co-activators and co-repressors modulate the activity of both ERα and ERRα. If co-activator or co-repressors are scarce, then competition for this supply between ERα and ERRα could alter the relative activity of each receptor. (C) ERRα can induce the transcription of several enzymes in the steroidogenic pathway. Ultimately, this may lead to increased estrogen levels and ERα activity.

Citation: Endocrine-Related Cancer Endocr Relat Cancer 13, Supplement_1; 10.1677/erc.1.01292

References

  • ApakTI & Duffel MW 2004 Interactions of the stereoisomers of alpha-hydroxytamoxifen with human hydroxysteroid sulfotransferase SULT2A1 and rat hydroxysteroid sulfotransferase STA. Drug Metabolism and Disposition321501–1508.

    • Search Google Scholar
    • Export Citation
  • AriaziEA Clark GM & Mertz JE 2002 Estrogen-related receptor alpha and estrogen-related receptor gamma associate with unfavorable and favorable biomarkers respectively in human breast cancer. Cancer Research626510–6518.

    • Search Google Scholar
    • Export Citation
  • BarryJB & Giguere V 2005 Epidermal growth factor-induced signaling in breast cancer cells results in selective target gene activation by orphan nuclear receptor estrogen-related receptor alpha. Cancer Research656120–6129.

    • Search Google Scholar
    • Export Citation
  • BonnelyeE & Aubin JE 2005 Estrogen receptor-related receptor alpha: a mediator of estrogen response in bone. Journal of Clinical Endocrinology and Metabolism903115–3121.

    • Search Google Scholar
    • Export Citation
  • BonnelyeE Meerdad L & Aubin JE 2001 The orphan receptor estrogen related receptor ERR alpha is highly expressed in osteoblasts and is required for bone formation. Bone28S87.

    • Search Google Scholar
    • Export Citation
  • BonnelyeE Kung V Laplace C Galson DL & Aubin JE 2002 Estrogen receptor-related receptor alpha impinges on the estrogen axis in bone: potential function in osteoporosis. Endocrinology1433658–3670.

    • Search Google Scholar
    • Export Citation
  • BookoutA & Mangelsdorf D 2006 Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network. Cell126789–799.

    • Search Google Scholar
    • Export Citation
  • BuschBB Stevens WC Martin R Ordentlich P Zhou S Sapp DW Horlick RA & Mohan R 2004 Identification of a selective inverse agonist for the orphan nuclear receptor estrogen-related receptor alpha. Journal of Medicinal Chemistry475593–5596.

    • Search Google Scholar
    • Export Citation
  • ChenS Zhou DJ Yang C & Sherman M 2001 Molecular basis for the constitutive activity of estrogen-related receptor alpha-1. Journal of Biological Chemistry27628465–28470.

    • Search Google Scholar
    • Export Citation
  • ClintonGM & Hua W 1997 Estrogen action in human ovarian cancer. Critical Reviews in Oncology Hematology251.

  • CornishJ Callon KE Naot D Palmano KP Banovic T Bava U Watson M Lin JM Tong PC Chen Q et al.2004 Lactoferrin is a potent regulator of bone cell activity and increases bone formation in vivo.Endocrinology1454366–4374.

    • Search Google Scholar
    • Export Citation
  • CowardP Lee D Hull MV Lehmann JM4-Hydroxyt & Lehmann JM 2001 4-Hydroxytamoxifen binds to and deactivates the estrogen-related receptor gamma. PNAS988880–8884.

    • Search Google Scholar
    • Export Citation
  • CuiY Parra I Zhang M Hilsenbeck SG Tsimelzon A Furukawa T Horii A Zhang Z-Y Nicholson RI & Fuqua SAW 2006 Elevated expression of mitogen-activated protein kinase phosphatase 3 in breast tumors: a mechanism of tamoxifen resistance. Cancer Research665950–5959.

    • Search Google Scholar
    • Export Citation
  • DeuschleU Heck S Kober I Bauer U & Balogh I. (Lion Bioscience AG) (2004). NR3B1 nuclear receptor-binding 3-substituted pyrazole derivatives and therapeutic uses. EP001398029A8.

  • EudyJD Yao S Weston MD Ma-Edmonds M Talmadge CB Cheng JJ Kimberling WJ & Sumegi J 1998 Isolation of a gene encoding a novel member of the nuclear receptor superfamily from the critical region of Usher syndrome type IIa at 1q41. Genomics50382–384.

    • Search Google Scholar
    • Export Citation
  • FelsonDT Zhang Y Hannan MT Kiel DP Wilson PWF & Anderson JJ 1993 The effect of postmenopausal estrogen therapy on bone density in elderly women. New England Journal of Medicine3291141–1146.

    • Search Google Scholar
    • Export Citation
  • GiguereV2002 To ERR in the estrogen pathway. Trends In Endocrinology And Metabolism13220–225.

  • GiguereV Yang N Segui P & Evans RM 1988 Identification of a new class of steroid hormone receptors. Nature33191–94.

  • GreschikH Wurtz J-M Sanglier S Bourguet W Dorsselaer AV Moras D & Renaud JP 2002 Structural and functional evidence for ligand-independent transcriptional activation by the estrogen-related receptor 3. Molecular Cell9303–313.

    • Search Google Scholar
    • Export Citation
  • GreschikH Flaig R Renaud JP & Moras D 2004 Structural basis for the deactivation of the estrogen-related receptor gamma by diethylstilbestrol or 4-hydroxytamoxifen and determinants of selectivity. Journal of Biological Chemistry27933639–33646.

    • Search Google Scholar
    • Export Citation
  • HussJM Torra IP Staels B Giguere V & Kelly DP 2004 Estrogen-related receptor alpha directs peroxisome proliferator-activated receptor at signaling in the transcriptional control of energy metabolism in cardiac and skeletal muscle. Molecular and Cellular Biology249079–9091.

    • Search Google Scholar
    • Export Citation
  • KallenJ Schlaeppi JM Bitsch F Filipuzzi I Schilb A Riou V Graham A Strauss A Geiser M & Fournier B 2004 Evidence for ligand-independent transcriptional activation of the human estrogen-related receptor alpha (ERR alpha) – Crystal structure of ERR alpha ligand binding domain in complex with peroxisome proliferator-activated receptor coactivator-1 alpha. Journal of Biological Chemistry27949330–49337.

    • Search Google Scholar
    • Export Citation
  • KameiY Lwin H Saito K Yokoyama T Yoshiike N Ezaki O & Tanaka H 2005 The 2.3 genotype of ESRRA23 of the ERR alpha gene is associated with a higher BMI than the 2.2 genotype. Obesity Research131843–1844.

    • Search Google Scholar
    • Export Citation
  • KatoS Endoh H Masuhiro Y Kitamoto T Uchiyama S Sasaki H Masushige S Gotoh Y Nishida E & Kawashima H 1995 Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science2701491–1494.

    • Search Google Scholar
    • Export Citation
  • KelleyDE He J Menshikova EV & Ritov VB 2002 Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes512944–2950.

    • Search Google Scholar
    • Export Citation
  • KrausRJ Ariazi EA Farrell ML & Mertz JE 2002 Estrogen-related receptor alpha 1 actively antagonizes estrogen receptor-regulated transcription in MCF-7 mammary cells. Journal of Biological Chemistry27724826–24834.

    • Search Google Scholar
    • Export Citation
  • LaflammeN Giroux S Loredo-Osti JC Elfassihi L Dodin S Blanchet C Morgan K Giguere V & Rousseau F 2005 A frequent regulatory variant of the estrogen-related receptor alpha gene associated with BMD in French–Canadian premenopausal women. Journal of Bone Mineral Research20938–944.

    • Search Google Scholar
    • Export Citation
  • LaudetV1997 Evolution of the nuclear receptor superfamily: early diversification from an ancestral orphan receptor. Journal of Molecular Endocrinology19207–226.

    • Search Google Scholar
    • Export Citation
  • LaudetV Hänni C Coll J Catzeflis F & Stéhelin D 1992 Evolution of the nuclear receptor gene superfamily. EMBO Journal111003–1013.

    • Search Google Scholar
    • Export Citation
  • LinJ Tarr PT Yang R Rhee J Puigserver P Newgard CB & Spiegelman BM 2003 PGC-1beta in the regulation of hepatic glucose and energy metabolism. Journal of Biological Chemistry27830843–30848.

    • Search Google Scholar
    • Export Citation
  • LinJ Yang R Tarr PT Wu P-H Handschin C Li S Yang W Pei L Uldry M Tontonoz P et al.2005 Hyperlipidemic effects of dietary saturated fats mediated through PGC-1 beta coactivation of SREBP. Cell120261–273.

    • Search Google Scholar
    • Export Citation
  • LowellBB & Shulman GI 2005 Mitochondrial dysfunction and type 2 diabetes. Science307384–387.

  • LuD Kiriyama Y Lee KY & Giguere V 2001 Transcriptional regulation of the estrogen-inducible pS2 breast cancer marker gene by the ERR family of orphan nuclear receptors. Cancer Research616755–6761.

    • Search Google Scholar
    • Export Citation
  • LuoJM Sladek R Carrier J Bader JA Richard D & Giguere V 2003 Reduced fat mass in mice lacking orphan nuclear receptor estrogen-related receptor alpha. Molecular and Cellular Biology237947–7956.

    • Search Google Scholar
    • Export Citation
  • McKennaNJ Lanz RB & O’Malley BW 1999 Nuclear receptor coregulators: cellular and molecular biology. Endocrine Reviews20321–344.

  • MoothaVK Lindgren CM Eriksson KF Subramanian A Sihag S Lehar J Puigserver P Carlsson E Ridderstrale M Laurila E et al.2003 PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nature Genetics34267–273.

    • Search Google Scholar
    • Export Citation
  • MoothaVK Handschin C Arlow D Xie XH Pierre J St Sihag S Yang WL Altshuler D Puigserver P Patterson N et al.2004 ERR alpha and Gabpa/b specify PGC-1 alpha-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle. PNAS1016570–6575.

    • Search Google Scholar
    • Export Citation
  • NolteRT Wang L Orband-Miller LA Way JM Martin JJ Roa AM Vela L Miller AB Willson TM & Zuercher WJ 2005 Identification and X-ray Crystal Structure of an ERR Alpha Inverse Agonist Reveals a New Mechanism of Nuclear Receptor Antagonism 230th American Chemical Society National Meeting Washington DC USA 2005.

  • OberkoflerH Linnemayr V Weitgasser R Klein K Xie M Iglseder B Krempler F Paulweber B & Patsch W 2004 Complex haplotypes of the PGC-1alpha gene are associated with carbohydrate metabolism and type 2 diabetes. Diabetes531385–1393.

    • Search Google Scholar
    • Export Citation
  • PlayerMR Pottorf RS Rentzeperis D & De D. (Johnson and Johnson) 2004 Use of estrogen related receptor-modulating aryl ethers. US. 2006014812.

  • PuigserverP & Spiegelman BM 2003 Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. Endocrine Reviews2478–90.

    • Search Google Scholar
    • Export Citation
  • RobertsonJF Cannon PM Nicholson RI & Blamey RW 1996 Oestrogen and progesterone receptors as prognostic variables in hormonally treated breast cancer. International Journal of Biological Markers1129–35.

    • Search Google Scholar
    • Export Citation
  • SeelyJ Amigh KS Suzuki T Mayhew B Sasano H Giguere V Laganiere J Carr BR & Rainey WE 2005 Transcriptional regulation of dehydroepiandrosterone sulfotransferase (SULT2A1) by estrogen-related receptor alpha. Endocrinology1463605–3613.

    • Search Google Scholar
    • Export Citation
  • SimpsonER2003 Sources of estrogen and their importance. Journal of Steroid Biochemistry and Molecular Biology86225–230.

  • SladekR Bader JA & Giguere V 1997 The orphan nuclear receptor estrogen-related receptor alpha is a transcriptional regulator of the human medium-chain acyl coenzyme A dehydrogenase gene. Molecular and Cellular Biology175400–5409.

    • Search Google Scholar
    • Export Citation
  • SuetsugiM Su L Karlsberg K Yuan YC & Chen S 2003 Flavone and isoflavone phytoestrogens are agonists of estrogen-related receptors. Molecular Cancer Research1981–991.

    • Search Google Scholar
    • Export Citation
  • SunP Sehouli J Denkert C Mustea A Konsgen D Koch I Wei L & Lichtenegger W 2005 Expression of estrogen receptor-related receptors a subfamily of orphan nuclear receptors as new tumor biomarkers in ovarian cancer cells. Journal of Molecular Medicine261699–1706.

    • Search Google Scholar
    • Export Citation
  • SuzukiT Miki Y Moriya T Shimada N Ishida T Hirakawa H Ohuchi N & Sasano H 2004 Estrogen-related receptor alpha in human breast carcinoma as a potent prognostic factor. Cancer Research644670–4676.

    • Search Google Scholar
    • Export Citation
  • TremblayGB Bergeron D & Giguere V 2001 4-Hydroxytamoxifen is an isoform-specific inhibitor of orphan estrogen-receptor-related (ERR) nuclear receptors beta and gamma. Endocrinology1424572–4575.

    • Search Google Scholar
    • Export Citation
  • VanackerJM Bonnelye E Chopin-Delannoy S Delmarre C Cavailles V & Laudet V 1999a Transcriptional activities of the orphan nuclear receptor ERR alpha (estrogen receptor-related receptor-alpha). Molecular Endocrinology13764–773.

    • Search Google Scholar
    • Export Citation
  • VanackerJM Pettersson K Gustafsson JA & Laudet V 1999b Transcriptional targets shared by estrogen receptor-related receptors (ERRs) and estrogen receptor (ER) alpha but not by ER beta. EMBO Journal184270–4279.

    • Search Google Scholar
    • Export Citation
  • WillyPJ Murray IR Qian J Busch BB Stevens WC Martin R Mohan R Zhou SH Ordentlich P Wei P et al.2004 Regulation of PPAR gamma coactivator 1 alpha (PGC-1 alpha) signaling by an estrogen-related receptor alpha (ERR alpha) ligand. PNAS1018912–8917.

    • Search Google Scholar
    • Export Citation
  • WuZ Puigserver P Andersson U Zhang C Adelmant G Mootha V Troy A Cinti S Lowell B Scarpulla RC et al.1999 Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell98115–124.

    • Search Google Scholar
    • Export Citation
  • XieW Hong H Yang NN Lin RJ Simon CM Stallcup MR & Evans RM 1999 Constitutive activation of transcription and binding of coactivator by estrogen-related receptors 1 and 2. Molecular Endocrinology132151–2162.

    • Search Google Scholar
    • Export Citation
  • YangC & Chen S 1999 Two organochlorine pesticides toxaphene and chlordane are antagonists for estrogen-related receptor alpha-1 orphan receptor. Cancer Research594519–4524.

    • Search Google Scholar
    • Export Citation
  • YangC Zhou DJ & Chen S 1998 Modulation of aromatase expression in the breast tissue by ERR alpha-1 orphan receptor. Cancer Research585695–5700.

    • Search Google Scholar
    • Export Citation
  • YangNY Shigeta H Shi HP & Teng CT 1996 Estrogen-related receptor hERR1 modulates estrogen receptor-mediated responses of human lactoferrin gene promoter. Journal of Biological Chemistry2715795–5804.

    • Search Google Scholar
    • Export Citation
  • YoonJC Puigserver P Chen G Donovan J Wu Z Rhee J Adelmant G Stafford J Khan CR Granner DK et al.2001 Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature413131–138.

    • Search Google Scholar
    • Export Citation

 

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Figures

  • View in gallery

    Amino acid identity between the ERs and ERRs within the DNA-binding domain (DBD) and the ligand-binding domain (LBD). Although several alternative splice variants of the ERRs have been identified, the total number of amino acids in the most common variant is shown above (Adapted from Laudet 1997, reproduced with permission from the Society for Endocrinology).

  • View in gallery

    (A) ERα and ERRα bind to similar promoter elements. Potentially, ERRα could substitute for ERα on an ERE, or a heterodimer formation could occur. The relative affinity for promoter binding and the transcriptional activity of ERRα are each likely to partially be determined by the entire promoter context. (B) Many nuclear receptor co-activators and co-repressors modulate the activity of both ERα and ERRα. If co-activator or co-repressors are scarce, then competition for this supply between ERα and ERRα could alter the relative activity of each receptor. (C) ERRα can induce the transcription of several enzymes in the steroidogenic pathway. Ultimately, this may lead to increased estrogen levels and ERα activity.

References

  • ApakTI & Duffel MW 2004 Interactions of the stereoisomers of alpha-hydroxytamoxifen with human hydroxysteroid sulfotransferase SULT2A1 and rat hydroxysteroid sulfotransferase STA. Drug Metabolism and Disposition321501–1508.

    • Search Google Scholar
    • Export Citation
  • AriaziEA Clark GM & Mertz JE 2002 Estrogen-related receptor alpha and estrogen-related receptor gamma associate with unfavorable and favorable biomarkers respectively in human breast cancer. Cancer Research626510–6518.

    • Search Google Scholar
    • Export Citation
  • BarryJB & Giguere V 2005 Epidermal growth factor-induced signaling in breast cancer cells results in selective target gene activation by orphan nuclear receptor estrogen-related receptor alpha. Cancer Research656120–6129.

    • Search Google Scholar
    • Export Citation
  • BonnelyeE & Aubin JE 2005 Estrogen receptor-related receptor alpha: a mediator of estrogen response in bone. Journal of Clinical Endocrinology and Metabolism903115–3121.

    • Search Google Scholar
    • Export Citation
  • BonnelyeE Meerdad L & Aubin JE 2001 The orphan receptor estrogen related receptor ERR alpha is highly expressed in osteoblasts and is required for bone formation. Bone28S87.

    • Search Google Scholar
    • Export Citation
  • BonnelyeE Kung V Laplace C Galson DL & Aubin JE 2002 Estrogen receptor-related receptor alpha impinges on the estrogen axis in bone: potential function in osteoporosis. Endocrinology1433658–3670.

    • Search Google Scholar
    • Export Citation
  • BookoutA & Mangelsdorf D 2006 Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network. Cell126789–799.

    • Search Google Scholar
    • Export Citation
  • BuschBB Stevens WC Martin R Ordentlich P Zhou S Sapp DW Horlick RA & Mohan R 2004 Identification of a selective inverse agonist for the orphan nuclear receptor estrogen-related receptor alpha. Journal of Medicinal Chemistry475593–5596.

    • Search Google Scholar
    • Export Citation
  • ChenS Zhou DJ Yang C & Sherman M 2001 Molecular basis for the constitutive activity of estrogen-related receptor alpha-1. Journal of Biological Chemistry27628465–28470.

    • Search Google Scholar
    • Export Citation
  • ClintonGM & Hua W 1997 Estrogen action in human ovarian cancer. Critical Reviews in Oncology Hematology251.

  • CornishJ Callon KE Naot D Palmano KP Banovic T Bava U Watson M Lin JM Tong PC Chen Q et al.2004 Lactoferrin is a potent regulator of bone cell activity and increases bone formation in vivo.Endocrinology1454366–4374.

    • Search Google Scholar
    • Export Citation
  • CowardP Lee D Hull MV Lehmann JM4-Hydroxyt & Lehmann JM 2001 4-Hydroxytamoxifen binds to and deactivates the estrogen-related receptor gamma. PNAS988880–8884.

    • Search Google Scholar
    • Export Citation
  • CuiY Parra I Zhang M Hilsenbeck SG Tsimelzon A Furukawa T Horii A Zhang Z-Y Nicholson RI & Fuqua SAW 2006 Elevated expression of mitogen-activated protein kinase phosphatase 3 in breast tumors: a mechanism of tamoxifen resistance. Cancer Research665950–5959.

    • Search Google Scholar
    • Export Citation
  • DeuschleU Heck S Kober I Bauer U & Balogh I. (Lion Bioscience AG) (2004). NR3B1 nuclear receptor-binding 3-substituted pyrazole derivatives and therapeutic uses. EP001398029A8.

  • EudyJD Yao S Weston MD Ma-Edmonds M Talmadge CB Cheng JJ Kimberling WJ & Sumegi J 1998 Isolation of a gene encoding a novel member of the nuclear receptor superfamily from the critical region of Usher syndrome type IIa at 1q41. Genomics50382–384.

    • Search Google Scholar
    • Export Citation
  • FelsonDT Zhang Y Hannan MT Kiel DP Wilson PWF & Anderson JJ 1993 The effect of postmenopausal estrogen therapy on bone density in elderly women. New England Journal of Medicine3291141–1146.

    • Search Google Scholar
    • Export Citation
  • GiguereV2002 To ERR in the estrogen pathway. Trends In Endocrinology And Metabolism13220–225.

  • GiguereV Yang N Segui P & Evans RM 1988 Identification of a new class of steroid hormone receptors. Nature33191–94.

  • GreschikH Wurtz J-M Sanglier S Bourguet W Dorsselaer AV Moras D & Renaud JP 2002 Structural and functional evidence for ligand-independent transcriptional activation by the estrogen-related receptor 3. Molecular Cell9303–313.

    • Search Google Scholar
    • Export Citation
  • GreschikH Flaig R Renaud JP & Moras D 2004 Structural basis for the deactivation of the estrogen-related receptor gamma by diethylstilbestrol or 4-hydroxytamoxifen and determinants of selectivity. Journal of Biological Chemistry27933639–33646.

    • Search Google Scholar
    • Export Citation
  • HussJM Torra IP Staels B Giguere V & Kelly DP 2004 Estrogen-related receptor alpha directs peroxisome proliferator-activated receptor at signaling in the transcriptional control of energy metabolism in cardiac and skeletal muscle. Molecular and Cellular Biology249079–9091.

    • Search Google Scholar
    • Export Citation
  • KallenJ Schlaeppi JM Bitsch F Filipuzzi I Schilb A Riou V Graham A Strauss A Geiser M & Fournier B 2004 Evidence for ligand-independent transcriptional activation of the human estrogen-related receptor alpha (ERR alpha) – Crystal structure of ERR alpha ligand binding domain in complex with peroxisome proliferator-activated receptor coactivator-1 alpha. Journal of Biological Chemistry27949330–49337.

    • Search Google Scholar
    • Export Citation
  • KameiY Lwin H Saito K Yokoyama T Yoshiike N Ezaki O & Tanaka H 2005 The 2.3 genotype of ESRRA23 of the ERR alpha gene is associated with a higher BMI than the 2.2 genotype. Obesity Research131843–1844.

    • Search Google Scholar
    • Export Citation
  • KatoS Endoh H Masuhiro Y Kitamoto T Uchiyama S Sasaki H Masushige S Gotoh Y Nishida E & Kawashima H 1995 Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science2701491–1494.

    • Search Google Scholar
    • Export Citation
  • KelleyDE He J Menshikova EV & Ritov VB 2002 Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes512944–2950.

    • Search Google Scholar
    • Export Citation
  • KrausRJ Ariazi EA Farrell ML & Mertz JE 2002 Estrogen-related receptor alpha 1 actively antagonizes estrogen receptor-regulated transcription in MCF-7 mammary cells. Journal of Biological Chemistry27724826–24834.

    • Search Google Scholar
    • Export Citation
  • LaflammeN Giroux S Loredo-Osti JC Elfassihi L Dodin S Blanchet C Morgan K Giguere V & Rousseau F 2005 A frequent regulatory variant of the estrogen-related receptor alpha gene associated with BMD in French–Canadian premenopausal women. Journal of Bone Mineral Research20938–944.

    • Search Google Scholar
    • Export Citation
  • LaudetV1997 Evolution of the nuclear receptor superfamily: early diversification from an ancestral orphan receptor. Journal of Molecular Endocrinology19207–226.

    • Search Google Scholar
    • Export Citation
  • LaudetV Hänni C Coll J Catzeflis F & Stéhelin D 1992 Evolution of the nuclear receptor gene superfamily. EMBO Journal111003–1013.

    • Search Google Scholar
    • Export Citation
  • LinJ Tarr PT Yang R Rhee J Puigserver P Newgard CB & Spiegelman BM 2003 PGC-1beta in the regulation of hepatic glucose and energy metabolism. Journal of Biological Chemistry27830843–30848.

    • Search Google Scholar
    • Export Citation
  • LinJ Yang R Tarr PT Wu P-H Handschin C Li S Yang W Pei L Uldry M Tontonoz P et al.2005 Hyperlipidemic effects of dietary saturated fats mediated through PGC-1 beta coactivation of SREBP. Cell120261–273.

    • Search Google Scholar
    • Export Citation
  • LowellBB & Shulman GI 2005 Mitochondrial dysfunction and type 2 diabetes. Science307384–387.

  • LuD Kiriyama Y Lee KY & Giguere V 2001 Transcriptional regulation of the estrogen-inducible pS2 breast cancer marker gene by the ERR family of orphan nuclear receptors. Cancer Research616755–6761.

    • Search Google Scholar
    • Export Citation
  • LuoJM Sladek R Carrier J Bader JA Richard D & Giguere V 2003 Reduced fat mass in mice lacking orphan nuclear receptor estrogen-related receptor alpha. Molecular and Cellular Biology237947–7956.

    • Search Google Scholar
    • Export Citation
  • McKennaNJ Lanz RB & O’Malley BW 1999 Nuclear receptor coregulators: cellular and molecular biology. Endocrine Reviews20321–344.

  • MoothaVK Lindgren CM Eriksson KF Subramanian A Sihag S Lehar J Puigserver P Carlsson E Ridderstrale M Laurila E et al.2003 PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nature Genetics34267–273.

    • Search Google Scholar
    • Export Citation
  • MoothaVK Handschin C Arlow D Xie XH Pierre J St Sihag S Yang WL Altshuler D Puigserver P Patterson N et al.2004 ERR alpha and Gabpa/b specify PGC-1 alpha-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle. PNAS1016570–6575.

    • Search Google Scholar
    • Export Citation
  • NolteRT Wang L Orband-Miller LA Way JM Martin JJ Roa AM Vela L Miller AB Willson TM & Zuercher WJ 2005 Identification and X-ray Crystal Structure of an ERR Alpha Inverse Agonist Reveals a New Mechanism of Nuclear Receptor Antagonism 230th American Chemical Society National Meeting Washington DC USA 2005.

  • OberkoflerH Linnemayr V Weitgasser R Klein K Xie M Iglseder B Krempler F Paulweber B & Patsch W 2004 Complex haplotypes of the PGC-1alpha gene are associated with carbohydrate metabolism and type 2 diabetes. Diabetes531385–1393.

    • Search Google Scholar
    • Export Citation
  • PlayerMR Pottorf RS Rentzeperis D & De D. (Johnson and Johnson) 2004 Use of estrogen related receptor-modulating aryl ethers. US. 2006014812.

  • PuigserverP & Spiegelman BM 2003 Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. Endocrine Reviews2478–90.

    • Search Google Scholar
    • Export Citation
  • RobertsonJF Cannon PM Nicholson RI & Blamey RW 1996 Oestrogen and progesterone receptors as prognostic variables in hormonally treated breast cancer. International Journal of Biological Markers1129–35.

    • Search Google Scholar
    • Export Citation
  • SeelyJ Amigh KS Suzuki T Mayhew B Sasano H Giguere V Laganiere J Carr BR & Rainey WE 2005 Transcriptional regulation of dehydroepiandrosterone sulfotransferase (SULT2A1) by estrogen-related receptor alpha. Endocrinology1463605–3613.

    • Search Google Scholar
    • Export Citation
  • SimpsonER2003 Sources of estrogen and their importance. Journal of Steroid Biochemistry and Molecular Biology86225–230.

  • SladekR Bader JA & Giguere V 1997 The orphan nuclear receptor estrogen-related receptor alpha is a transcriptional regulator of the human medium-chain acyl coenzyme A dehydrogenase gene. Molecular and Cellular Biology175400–5409.

    • Search Google Scholar
    • Export Citation
  • SuetsugiM Su L Karlsberg K Yuan YC & Chen S 2003 Flavone and isoflavone phytoestrogens are agonists of estrogen-related receptors. Molecular Cancer Research1981–991.

    • Search Google Scholar
    • Export Citation
  • SunP Sehouli J Denkert C Mustea A Konsgen D Koch I Wei L & Lichtenegger W 2005 Expression of estrogen receptor-related receptors a subfamily of orphan nuclear receptors as new tumor biomarkers in ovarian cancer cells. Journal of Molecular Medicine261699–1706.

    • Search Google Scholar
    • Export Citation
  • SuzukiT Miki Y Moriya T Shimada N Ishida T Hirakawa H Ohuchi N & Sasano H 2004 Estrogen-related receptor alpha in human breast carcinoma as a potent prognostic factor. Cancer Research644670–4676.

    • Search Google Scholar
    • Export Citation
  • TremblayGB Bergeron D & Giguere V 2001 4-Hydroxytamoxifen is an isoform-specific inhibitor of orphan estrogen-receptor-related (ERR) nuclear receptors beta and gamma. Endocrinology1424572–4575.

    • Search Google Scholar
    • Export Citation
  • VanackerJM Bonnelye E Chopin-Delannoy S Delmarre C Cavailles V & Laudet V 1999a Transcriptional activities of the orphan nuclear receptor ERR alpha (estrogen receptor-related receptor-alpha). Molecular Endocrinology13764–773.

    • Search Google Scholar
    • Export Citation
  • VanackerJM Pettersson K Gustafsson JA & Laudet V 1999b Transcriptional targets shared by estrogen receptor-related receptors (ERRs) and estrogen receptor (ER) alpha but not by ER beta. EMBO Journal184270–4279.

    • Search Google Scholar
    • Export Citation
  • WillyPJ Murray IR Qian J Busch BB Stevens WC Martin R Mohan R Zhou SH Ordentlich P Wei P et al.2004 Regulation of PPAR gamma coactivator 1 alpha (PGC-1 alpha) signaling by an estrogen-related receptor alpha (ERR alpha) ligand. PNAS1018912–8917.

    • Search Google Scholar
    • Export Citation
  • WuZ Puigserver P Andersson U Zhang C Adelmant G Mootha V Troy A Cinti S Lowell B Scarpulla RC et al.1999 Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell98115–124.

    • Search Google Scholar
    • Export Citation
  • XieW Hong H Yang NN Lin RJ Simon CM Stallcup MR & Evans RM 1999 Constitutive activation of transcription and binding of coactivator by estrogen-related receptors 1 and 2. Molecular Endocrinology132151–2162.

    • Search Google Scholar
    • Export Citation
  • YangC & Chen S 1999 Two organochlorine pesticides toxaphene and chlordane are antagonists for estrogen-related receptor alpha-1 orphan receptor. Cancer Research594519–4524.

    • Search Google Scholar
    • Export Citation
  • YangC Zhou DJ & Chen S 1998 Modulation of aromatase expression in the breast tissue by ERR alpha-1 orphan receptor. Cancer Research585695–5700.

    • Search Google Scholar
    • Export Citation
  • YangNY Shigeta H Shi HP & Teng CT 1996 Estrogen-related receptor hERR1 modulates estrogen receptor-mediated responses of human lactoferrin gene promoter. Journal of Biological Chemistry2715795–5804.

    • Search Google Scholar
    • Export Citation
  • YoonJC Puigserver P Chen G Donovan J Wu Z Rhee J Adelmant G Stafford J Khan CR Granner DK et al.2001 Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature413131–138.

    • Search Google Scholar
    • Export Citation

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