ESRRA (estrogen-related receptor alpha)

2009-07-01   Rebecca Stein Kunder , Donald P McDonnell 

Department of Pharmacology, Cancer Biology, Duke University Medical Center, Box 3813, Durham, NC 27710, USA





-Sequence length 11,172 bases;
-CDS: 2221;
-Exons: 7.


Alternative splicing results in transcript variants, but these have not yet been well-characterized.


A pseudogene has been reported, ESRRAP, located at 13q12.1. However, it is possible that this pseudogene is not transcribed (Sladek et al., 1997).


Atlas Image
Schematic of nuclear receptor structure and function.
ERRa is a member of the nuclear receptor (NR) superfamily of transcription factors and is most closely related to estrogen receptor alpha (ERa). The modular structure of NRs consists of seven (A-F) domains. The A/B region, which harbors activation function 1 (AF-1), is not well-conserved across NRs, but regions C and E are highly conserved and harbor, respectively, the DNA-binding domain (DBD) and ligand-binding domain (LBD). ERRa shares with ERa 68% sequence identity within the DBD and 33% within the LBD. The functional regions of the DBD have been finely mapped. In addition to two zinc finger motifs, this domain contains a Proximal-box (P-box) which determines DNA sequence specificity, and a Dimerization-box (D-box), which part of the dimerization interface.


ERRa is a 45.5 kDa, 423 amino acid orphan nuclear receptor. Although closely related to the estrogen receptors, its transcriptional activity is regulated to any significant degree by estrogens. ERRa binds to specific DNA sequences within target gene promoters as a monomer or homodimer and recruits coactivating proteins, the best known of which is PGC-1a.


ERRa is ubiquitously expressed throughout development with the highest levels of expression in tissues that oxidize fatty acids such as kidney, heart, cerebellum, intestine and skeletal muscle (nursa).


ERRa is thought to be predominately nuclear, although recently it has been reported to be perinuclear and cytoplasmic in breast cancer tissue (Jarzabek et al., 2009).


The function of ERRa as a metabolic regulator is supported by the observation that erra-null mice demonstrate impaired fat metabolism and absorption (Luo et al., 2003). It has recently been demonstrated that erra-null mice also have a reduced capacity for adaptation to hemodynamic stressors. Due to this functional deficit, these mice often develop cardiac contractile dysfunction. The cardiac remodeling under stress in ERR-null mice is due to defects in ATP synthesis and reduced phosphocreatine stores, which are both characteristic of pathologic cardiac hypertrophy (Huss et al., 2007). That the expression of ERRa is elevated in exercising muscle and in fasting liver specifically implicates this receptor in beta-oxidation of fatty acids, a metabolic pathway that is highly active under these conditions. On a mechanistic level, several studies have revealed that ERRa is involved in the transcriptional regulation of genes required for mitochondrial biogenesis, oxidative phosphorylation and fatty acid oxidation (Huss et al., 2004; Mootha et al., 2004; Dufour et al., 2007).
Thus far, metabolic studies of ERRa function have mainly focused on its role as the downstream effector of PGC-1a. PGC-1a is a promiscuous nuclear receptor coactivator expressed at low basal levels but induced by fasting and other metabolic stresses (Puigserver and Spiegelman, 2003). PGC-1beta, a related cofactor, may have similar functions, although its expression level is not as acutely regulated by variations in energy demand (Yoon et al., 2001). Rather than being regulated by ligand, the magnitude of ERRa activity is thought to be largely dependent on the presence of transcriptional coactivators such as PGC-1a and beta. Interest in the ERR-PGC-1 regulatory axis was heightened by the observation that there is a decrease in both PGC-1a and PGC-1beta in the skeletal muscle of patients with diabetes and obesity (Mootha et al., 2003).


Sequence analysis reveals that the ERRs and the classical estrogen receptors share a high degree of homology within their DNA and ligand binding domains. In particular, ERRa shares with ERa approximately 68% sequence identity within the DNA binding domain and 33% within the ligand binding domains. This relationship provides a structural basis both for the conserved nature of DNA binding and the divergence in hormone binding between these two receptors.



Although over 80 SNPs have been reported, only one variant has been shown to carry clinical associations.
Laflamme et al. reported a polymoprohic hormone response element within the ESRRA promoter (Laflamme et al., 2005). The variant sequence, present in 11% of the population tested (white, premenopausal women), included an ERRa responsive element within the additional 23-nucelotides. This longer variant was associated with higher bone mineral density measured in the lumbar spine.
Kamei et al. reported that the longer variant is associated with a significantly higher body mass index in their study population of 729 Japanese men and women (Kamie et al., 2005).

Implicated in

Entity name
Breast cancer
Two independent clinical studies have implicated ERRa in breast cancer progression (Ariazi et al., 2002; Suzuki et al., 2004). In the first study to link ERRa to clinical and pathological characteristics of breast cancer, Ariazi et al. found that ERRa expression is significantly associated with ERa-negative and progesterone receptor-negative tumor status as well as Her2 status. Further exploring the relationship between ERRa and Her2, Barry et al. demonstrated that ERRa transcriptional activity can be enhanced by phosphorylation events downstream of Her2 (Barry and Giguere, 2005). Building on the association between ERRa and negative prognostic biomarkers, Suzuki et al. demonstrated a direct correlation between ERRa expression and unfavorable breast cancer patient outcomes including increased tumor recurrence and decreased survival (Suzuki et al., 2004). Importantly, the predictive value of ERRa expression was shown to be independent of ERa status, confirming that targeting the ERRa pathway may be of therapeutic benefit in patients with either ERa-positive or ERa-negative breast cancer.
Recently, the function of ERRa has been evaluated in xenograft models of breast cancer. Stein et al. demonstrated that ERRa is critical for the growth of ERa-negative breast cancer through use of RNAi (Stein et al. 2008). Furthermore, Chisamore and coworkers found that an ERRa antagonist inhibited the growth of ERa-positive and ERa-negative breast cancer cell lines in a xenograft model (Chisamore et al., 2009).
Entity name
Ovarian cancer
Sun et al. demonstrated that the ovarian tumors had significantly higher ERRa mRNA levels than normal ovaries and that high ERRa expression correlated with clinically advanced and histologically aggressive disease. Furthermore, ERRa expression was shown to be an independent prognostic factor for poor overall patient survival (Sun et al., 2005).
Entity name
Colorectal cancer
Analysis of 80 colorectal tumor samples demonstrated that higher levels of ERRa mRNA are expressed in tumor tissue versus in the surrounding normal mucosa. Furthermore, tumor tissue ERRa mRNA levels are positively correlated with increased tumor stage and histological grade (Cavallini et al., 2005).
Entity name
Prostate cancer
Cheung et al. investigated the expression patterns of the three ERR family members in normal and malignant human prostate epithelial cells and cell lines (Cheung et al., 2005). The authors also characterized ERR protein expression and localization in normal, dysplastic, and malignant prostate tissue (Cheung et al., 2005). They concluded that ERRbeta and ERRgamma protein expression is reduced in neoplastic prostatic cells versus their non-malignant counterparts and suggested that each is down-regulated in the progression of prostate cancer. The authors went on to measure the effect of overexpressing the ERRs on proliferation of an immortalized prostate cell line and a prostate cancer cell line in vitro and on prostate cancer xenograft growth in vivo (Yu et al., 2007; Yu et al., 2008). They found that ERRbeta and ERRgamma can inhibit proliferation in cells derived from normal and malignant prostate epithelium by inducing a G1-S cell cycle arrest. Furthermore, activation of either ERRbeta or ERRgamma using the agonist DY131 resulted in a decreased rate of prostate tumor growth in a xenograft model.
Entity name
Endometrial cancer
Gao et al. explored the extent to which the ERRs are involved in ERa-positive endometrial adenocarcinoma (Gao et al., 2006). They measured the expression of each ERR family member in malignant versus normal endometrium and compared the expression levels to clinical and pathologic features. They concluded that the expression of ERRa mRNA was lower in ERa-positive endometrial adenocarcinoma versus normal endometrium. However, they also found that ERRa mRNA expression was positively correlated with tumor stage and myometrial invasion. Additionally Gao et al. found that the expression of ERRgamma mRNA was increased in endometrial adenocarcinoma compared to normal endometrium.





Pubmed IDLast YearTitleAuthors
185090532008Involvement of estrogen-related receptors in transcriptional response to hypoxia and growth of solid tumors.Ao A et al
182881962008HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1alpha.Arany Z et al
124382452002Estrogen-related receptor alpha and estrogen-related receptor gamma associate with unfavorable and favorable biomarkers, respectively, in human breast cancer.Ariazi EA et al
165154772006Estrogen-related receptors as emerging targets in cancer and metabolic disorders.Ariazi EA et al
172593472007Estrogen-related receptor alpha1 transcriptional activities are regulated in part via the ErbB2/HER2 signaling pathway.Ariazi EA et al
160246132005Epidermal growth factor-induced signaling in breast cancer cells results in selective target gene activation by orphan nuclear receptor estrogen-related receptor alpha.Barry JB et al
155091542004Identification of a selective inverse agonist for the orphan nuclear receptor estrogen-related receptor alpha.Busch BB et al
159499362005Oestrogen receptor-related receptor alpha (ERRalpha) and oestrogen receptors (ERalpha and ERbeta) exhibit different gene expression in human colorectal tumour progression.Cavallini A et al
155986862005Expression and functional study of estrogen receptor-related receptors in human prostatic cells and tissues.Cheung CP et al
192761592009Estrogen-related receptor-alpha antagonist inhibits both estrogen receptor-positive and estrogen receptor-negative breast tumor growth in mouse xenografts.Chisamore MJ et al
174886372007Genome-wide orchestration of cardiac functions by the orphan nuclear receptors ERRalpha and gamma.Dufour CR et al
175098762007Clinical implication of estrogen-related receptor (ERR) expression in ovarian cancers.Fujimoto J et al
172944522007Increased expression of estrogen-related receptor alpha (ERRalpha) is a negative prognostic predictor in human prostate cancer.Fujimura T et al
170530402007Definition of the molecular basis for estrogen receptor-related receptor-alpha-cofactor interactions.Gaillard S et al
166817692006Expression of estrogen receptor-related receptor isoforms and clinical significance in endometrial adenocarcinoma.Gao M et al
32672071988Identification of a new class of steroid hormone receptors.Giguère V et al
121856692002To ERR in the estrogen pathway.Giguère V et al
146646992003Estrogen receptor-related receptors: orphan receptors desperately seeking a ligand.Horard B et al
181741572008Estrogen induces estrogen-related receptor alpha gene expression and chromatin structural changes in estrogen receptor (ER)-positive and ER-negative breast cancer cells.Hu P et al
176188542007The nuclear receptor ERRalpha is required for the bioenergetic and functional adaptation to cardiac pressure overload.Huss JM et al
153750232004Nuclear receptor signaling and cardiac energetics.Huss JM et al
154568812004Estrogen-related receptor alpha directs peroxisome proliferator-activated receptor alpha signaling in the transcriptional control of energy metabolism in cardiac and skeletal muscle.Huss JM et al
180520882007On the intractability of estrogen-related receptor alpha as a target for activation by small molecules.Hyatt SM et al
191387402009The significance of the expression of ERRalpha as a potential biomarker in breast cancer.Jarzabek K et al
90583801997Estrogen-related receptor alpha 1 functionally binds as a monomer to extended half-site sequences including ones contained within estrogen-response elements.Johnston SD et al
162865342005The 2.3 genotype of ESRRA23 of the ERR alpha gene is associated with a higher BMI than the 2.2 genotype.Kamei Y et al
145303912003PPARgamma coactivator 1beta/ERR ligand 1 is an ERR protein ligand, whose expression induces a high-energy expenditure and antagonizes obesity.Kamei Y et al
158836332005A frequent regulatory variant of the estrogen-related receptor alpha gene associated with BMD in French-Canadian premenopausal women.Laflamme N et al
149780332004A polymorphic autoregulatory hormone response element in the human estrogen-related receptor alpha (ERRalpha) promoter dictates peroxisome proliferator-activated receptor gamma coactivator-1alpha control of ERRalpha expression.Laganière J et al
176314922007Potentiation of ICI182,780 (Fulvestrant)-induced estrogen receptor-alpha degradation by the estrogen receptor-related receptor-alpha inverse agonist XCT790.Lanvin O et al
129600792003Estrogen stimulates estrogen-related receptor alpha gene expression through conserved hormone response elements.Liu D et al
115595472001Transcriptional regulation of the estrogen-inducible pS2 breast cancer marker gene by the ERR family of orphan nuclear receptors.Lu D et al
145859562003Reduced fat mass in mice lacking orphan nuclear receptor estrogen-related receptor alpha.Luo J et al
151004102004Erralpha and Gabpa/b specify PGC-1alpha-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle.Mootha VK et al
128084572003PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes.Mootha VK et al
150875032004The estrogen-related receptor alpha (ERRalpha) functions in PPARgamma coactivator 1alpha (PGC-1alpha)-induced mitochondrial biogenesis.Schreiber SN et al
92867001997Human estrogen receptor-like 1 (ESRL1) gene: genomic organization, chromosomal localization, and promoter characterization.Shi H et al
93446551997Chromosomal mapping of the human and murine orphan receptors ERRalpha (ESRRA) and ERRbeta (ESRRB) and identification of a novel human ERRalpha-related pseudogene.Sladek R et al
176710902007Nuclear receptor ERR alpha and coactivator PGC-1 beta are effectors of IFN-gamma-induced host defense.Sonoda J et al
189741232008Estrogen-related receptor alpha is critical for the growth of estrogen receptor-negative breast cancer.Stein RA et al
172595552006Estrogen-related receptor alpha as a therapeutic target in cancer.Stein RA et al
157704982005Expression of estrogen receptor-related receptors, a subfamily of orphan nuclear receptors, as new tumor biomarkers in ovarian cancer cells.Sun P et al
170100742006An estrogen receptor alpha-dependent regulation of estrogen receptor-related receptor alpha in the proliferation of endometrial carcinoma cells.Sun PM et al
152316802004Estrogen-related receptor alpha in human breast carcinoma as a potent prognostic factor.Suzuki T et al
180636932008Phosphorylation-dependent sumoylation regulates estrogen-related receptor-alpha and -gamma transcriptional activity through a synergy control motif.Tremblay AM et al
103193261999Transcriptional activities of the orphan nuclear receptor ERR alpha (estrogen receptor-related receptor-alpha).Vanacker JM et al
93955111997A role for estrogen-related receptor alpha in the control of mitochondrial fatty acid beta-oxidation during brown adipocyte differentiation.Vega RB et al
187789512008ERRalpha: a metabolic function for the oldest orphan.Villena JA et al
176769302007Phosphorylation-dependent sumoylation of estrogen-related receptor alpha1.Vu EH et al
191711402009Kaempferol is an estrogen-related receptor alpha and gamma inverse agonist.Wang J et al
164649512006Function of estrogen-related receptor alpha in human endometrial cancer.Watanabe A et al
105985881999Constitutive activation of transcription and binding of coactivator by estrogen-related receptors 1 and 2.Xie W et al
104934991999Two organochlorine pesticides, toxaphene and chlordane, are antagonists for estrogen-related receptor alpha-1 orphan receptor.Yang C et al
98657251998Modulation of aromatase expression in the breast tissue by ERR alpha-1 orphan receptor.Yang C et al
115579722001Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1.Yoon JC et al
180713052008Orphan nuclear receptor estrogen-related receptor-beta suppresses in vitro and in vivo growth of prostate cancer cells via p21(WAF1/CIP1) induction and as a potential therapeutic target in prostate cancer.Yu S et al
171579802007Interplay between estrogen-related receptor alpha (ERRalpha) and gamma (ERRgamma) on the regulation of ERRalpha gene expression.Zhang Z et al
182349092008Estrogen receptor-related receptor alpha (ERRalpha) regulates osteopontin expression through a non-canonical ERRalpha response element in a cell context-dependent manner.Zirngibl RA et al

Other Information

Locus ID:

NCBI: 2101
MIM: 601998
HGNC: 3471
Ensembl: ENSG00000173153


dbSNP: 2101
ClinVar: 2101
TCGA: ENSG00000173153


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Organelle biogenesis and maintenanceREACTOMER-HSA-1852241
Mitochondrial biogenesisREACTOMER-HSA-1592230
Transcriptional activation of mitochondrial biogenesisREACTOMER-HSA-2151201
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Nuclear Receptor transcription pathwayREACTOMER-HSA-383280
Metabolism of lipids and lipoproteinsREACTOMER-HSA-556833
Fatty acid, triacylglycerol, and ketone body metabolismREACTOMER-HSA-535734
Regulation of lipid metabolism by Peroxisome proliferator-activated receptor alpha (PPARalpha)REACTOMER-HSA-400206
PPARA activates gene expressionREACTOMER-HSA-1989781


Pubmed IDYearTitleCitations
125221042003The transcriptional coactivator PGC-1 regulates the expression and activity of the orphan nuclear receptor estrogen-related receptor alpha (ERRalpha).134
187789512008ERRalpha: a metabolic function for the oldest orphan.91
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
152316802004Estrogen-related receptor alpha in human breast carcinoma as a potent prognostic factor.72
190618962009PGC-1alpha and ERRalpha target gene downregulation is a signature of the failing human heart.72
196227632009Genome-wide identification of direct target genes implicates estrogen-related receptor alpha as a determinant of breast cancer heterogeneity.65
153377442004Evidence for ligand-independent transcriptional activation of the human estrogen-related receptor alpha (ERRalpha): crystal structure of ERRalpha ligand binding domain in complex with peroxisome proliferator-activated receptor coactivator-1alpha.61
189741232008Estrogen-related receptor alpha is critical for the growth of estrogen receptor-negative breast cancer.57
208707442010WNT11 expression is induced by estrogen-related receptor alpha and beta-catenin and acts in an autocrine manner to increase cancer cell migration.53
220145752011The metabolic regulator ERRα, a downstream target of HER2/IGF-1R, as a therapeutic target in breast cancer.53


Rebecca Stein Kunder ; Donald P McDonnell

ESRRA (estrogen-related receptor alpha)

Atlas Genet Cytogenet Oncol Haematol. 2009-07-01

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