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Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA

(Requests for offprints should be addressed to D P McDonnell; Email: donald.mcdonnell{at}duke.edu)

This paper was presented at the 2nd Tenovus/AstraZeneca Workshop, Cardiff (2006). AstraZeneca supported the meeting and the Welsh School of Pharmacy, Cardiff University has supported the publication of these proceedings.

	Abstract

Top Abstract Introduction The estrogen receptor-signaling... Overview of estrogen-related... Indirect crosstalk between... Insights into ERR{alpha}... The emerging role of... ERR{alpha} in energy... Pharmacologic regulation of... Further development of... References

 
The orphan receptor estrogen-related receptor (ERR) 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 ERR as a therapeutic target in both breast and ovarian cancer and in other estrogenopathies. This review details our present understanding of ERR action with a view to highlight specific aspects of its signal-transduction pathway in breast cancer that may be amenable to pharmaceutical manipulation.

	Introduction

Top Abstract Introduction The estrogen receptor-signaling... Overview of estrogen-related... Indirect crosstalk between... Insights into ERR{alpha}... The emerging role of... ERR{alpha} in energy... Pharmacologic regulation of... Further development of... References

 
Drugs that function by inhibiting ER 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 ER-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 ER-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 ERR pathway and classical estrogen signaling and evaluate the present evidence supporting a role for ERR in breast cancer. Finally, we will identify key obstacles and questions that must be resolved if ERR is to be utilized as a therapeutic target in breast cancer.

	The estrogen receptor-signaling pathway

Top Abstract Introduction The estrogen receptor-signaling... Overview of estrogen-related... Indirect crosstalk between... Insights into ERR{alpha}... The emerging role of... ERR{alpha} in energy... Pharmacologic regulation of... Further development of... References

 
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: ER and ERß. 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 ER action. The specific roles of ERß 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 ER 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 ER (McKenna et al. 1999). The activity of ER 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). ER 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 ER presents a potential avenue through which other nuclear receptors including the ERRs may influence ER. More generally, the entire complicated web of ER regulation introduces numerous opportunities for the pharmacologic regulation of its activity.

	Overview of estrogen-related receptors

Top Abstract Introduction The estrogen receptor-signaling... Overview of estrogen-related... Indirect crosstalk between... Insights into ERR{alpha}... The emerging role of... ERR{alpha} in energy... Pharmacologic regulation of... Further development of... References

 
In 1988, Giguere et al.(1988) cloned the first orphan receptors, ERR and ERRß, using the DNA-binding domain (DBD) of ER as a probe to screen recombinant DNA libraries. A third isoform, ERR, 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, ERR shares with ER 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 ERR and ER.

View larger version (33K): [in this window] [in a new window]   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).

The transcriptional activity of several endogenous genes is regulated by both ERR and ER, 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 ERR can activate ER 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 ERR in the development and maintenance of tumors, but also raised the possibility that ERR 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, ERR can repress ligand-activated ER-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 ER and ERR 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 ER and ER target genes that contain an ERE within their promoters is significantly blunted when there is coincident high levels of ERR expression. In contrast, the correlation between ER and genes thought to be regulated by ER binding to a non-canonical ERE is not altered by ERR expression. Importantly, gel shift assays performed by Krause et al. verified that ER and ERR can compete directly for promoter binding in MCF7 cells. They went on to show that this is not merely a passive process but that ERR recruits co-repressor proteins that actively suppress the expression of ER 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 ERR can alter its activity. Of particular relevance, it has been shown that phosphorylation of ERR, 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 ERR-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 ERR (discussed only at meetings thus far) should provide the information needed to define the extent of overlap in genes regulated by these two receptors.

View larger version (39K): [in this window] [in a new window]   Figure 2 (A) ER and ERR bind to similar promoter elements. Potentially, ERR could substitute for ER on an ERE, or a heterodimer formation could occur. The relative affinity for promoter binding and the transcriptional activity of ERR 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 ER and ERR. If co-activator or co-repressors are scarce, then competition for this supply between ER and ERR could alter the relative activity of each receptor. (C) ERR can induce the transcription of several enzymes in the steroidogenic pathway. Ultimately, this may lead to increased estrogen levels and ER activity.

	Indirect crosstalk between ERR and ER

Top Abstract Introduction The estrogen receptor-signaling... Overview of estrogen-related... Indirect crosstalk between... Insights into ERR{alpha}... The emerging role of... ERR{alpha} in energy... Pharmacologic regulation of... Further development of... References

	Insights into ERR–ER crosstalk from studies in bone

Top Abstract Introduction The estrogen receptor-signaling... Overview of estrogen-related... Indirect crosstalk between... Insights into ERR{alpha}... The emerging role of... ERR{alpha} in energy... Pharmacologic regulation of... Further development of... References

 
Bone development and maintenance is an additional potential point of convergence between ER and ERR as these receptors are co-expressed in osteoblasts in vivo and in vitro (Bonnelye et al. 2002). The importance of ER 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). ERR is expressed throughout osteoblast development, and in vitro bone nodule formation can be inhibited by knocking down ERR expression (Bonnelye et al. 2001). Furthermore, a polymorphism has recently been discovered within the ERR 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 ERR protein. Given the potential regulation of steroidogenesis by ERR discussed above, ERR activity may serve to enhance ER signaling, leading to improved bone maintenance. Alternately, it may serve to activate ER target genes in bone in the absence of estrogen as indicated by the finding that the shared ER and ERR target lactoferrin promotes bone formation in vivo and protects osteoblasts from apoptosis in vitro (Yang et al. 1996, Cornish et al. 2004). ERR also may afford protection from bone loss independent of ER 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 ER and ERR, their specific roles in physiology and pathology require further investigation.

	The emerging role of ERR in cancer

Top Abstract Introduction The estrogen receptor-signaling... Overview of estrogen-related... Indirect crosstalk between... Insights into ERR{alpha}... The emerging role of... ERR{alpha} in energy... Pharmacologic regulation of... Further development of... References

 
In recent years, two independent clinical studies have implicated ERR in breast cancer progression (Ariazi et al. 2002, Suzuki et al. 2004). Analysis of 102 breast cancer samples revealed that the expression of ERR 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, ERR was found to be an independent prognostic factor controlling for factors, including ER status. Although in this study there was no correlation between ERR and ER expression, an earlier study by Ariazi et al. demonstrated that high levels of ERR mRNA correlated with ER-negative tumor status in the 38 tumors examined. Analysis of the other ERRs revealed that high expression of ERR correlates with positive outcomes for patients with breast cancer suggesting an opposing role to that of ERR (Ariazi et al. 2002).

Following the studies implicating ERR 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 ERR and postulated that ERR may play an important role by modulating ER 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 ERR mRNA levels detectable by quantitative real-time PCR. Furthermore, a positive correlation between ERR expression and advanced tumor stage and grade was observed. Notably, multivariate analysis implicated ERR expression as an independent prognostic factor for poor overall patient survival. In contrast to the success of targeting ER 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 ER likely plays an essential role in ovarian cancer. However, only 15–20% of patients with ER-positive tumors show a clinical response to anti-estrogens (Clinton & Hua 1997). Given the potential crosstalk between the estrogen-signaling pathway and that of ERR, it is tempting to speculate that ERR may be part of the explanation for the common resistance of ovarian cancers to ER blockade.

	ERR in energy homeostasis: a potential link to cancer?

Top Abstract Introduction The estrogen receptor-signaling... Overview of estrogen-related... Indirect crosstalk between... Insights into ERR{alpha}... The emerging role of... ERR{alpha} in energy... Pharmacologic regulation of... Further development of... References

 
From what is presently known about ERR, it appears that it may have two distinct functional activities in the cell. ERR 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 ERR as a modulator of ER signaling (Giguere 2002). How, and if, these activities are linked in the pathogenesis of cancers expressing ERR remains an open question.

In considering the potential for targeting the ERR 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 ERR in the mouse provided the first clue that ERR may regulate metabolic activity. Almost all organs express ERR 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 ERR as a metabolic regulator is further supported by the observation that ERR-null mice demonstrate impaired fat metabolism and absorption (Luo et al. 2003). That the expression of ERR is elevated in exercising muscle and fasting liver specifically implicates this receptor in ß-oxidation of fatty acids, which occurs under the same conditions. On a mechanistic level, several studies have revealed that ERR 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 ERR focus on its role as the downstream effector of PPAR co-activator 1 (PGC-1). PGC-1 is a promiscuous nuclear receptor co-activator expressed at low basal levels but induced by fasting and other metabolic stresses (Puigserver & Spiegelman 2003). PGC-1ß, 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 ERR activity is thought to be largely dependent on the presence of transcriptional co-activators, such as PGC-1 and PGC-1ß. Interest in the ERR–PGC-1 regulatory axis was heightened by the observation that there is a decrease in both PGC-1 and PGC-1ß 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 ERR promoter thought to sensitize ERR to PGC-1 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 ERR activity in both energy metabolism and tumor biology be understood if we are to further develop ERR as a therapeutic target.

	Pharmacologic regulation of ERR activity

Top Abstract Introduction The estrogen receptor-signaling... Overview of estrogen-related... Indirect crosstalk between... Insights into ERR{alpha}... The emerging role of... ERR{alpha} in energy... Pharmacologic regulation of... Further development of... References

 
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-ERR and apo-ERR 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 ERR 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 ERR 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 ERR 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 ERR inverse agonist which was subsequently optimized to the ERR-selective XCT790 (Busch et al. 2004). This thiadiazole-based compound inhibits ERR activity in transfection assays with submicromolar activity, and has been used to further define the role of ERR in the regulation of metabolic signaling pathways (Mootha et al. 2004, Willy et al. 2004). Several other ERR 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 ERRß and ERR 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 ERR peptide antagonists. These peptides bind with high affinity to ERR and block co-activator binding (S Gaillard & DP McDonnell, unpublished observations). In contrast to the numerous ERR antagonists reported, few natural or synthetic agonists of ERR 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 ERR activity using alternative strategies, such as altering the phosphorylation status of the receptor or targeting other upstream regulators of ERR.

	Further development of ERR as a therapeutic target

Top Abstract Introduction The estrogen receptor-signaling... Overview of estrogen-related... Indirect crosstalk between... Insights into ERR{alpha}... The emerging role of... ERR{alpha} in energy... Pharmacologic regulation of... Further development of... References

 
A clear understanding of ERR activity is likely to shed light on unresolved aspects of ER signaling and pharmacology and may validate ERR as a useful therapeutic target in breast cancer. Ultimately, if we are to pharmacologically manipulate ERR in the setting of metabolic disorders or cancer, we must determine if ERR expression and activity is a cause or consequence of the underlying pathology. Regarding the role of ERR in breast cancer, larger clinical studies as well as investigation into the molecular mechanism of ERR function in this particular setting are essential. The extent to which ERR signaling is intertwined with that of ER and the extent to which ERR 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 ERR as a therapeutic target within the settings of malignancy and metabolic disorders.

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Top Abstract Introduction The estrogen receptor-signaling... Overview of estrogen-related... Indirect crosstalk between... Insights into ERR{alpha}... The emerging role of... ERR{alpha} in energy... Pharmacologic regulation of... Further development of... References

 
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