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Endocrinology |
Molecular Oncology Group, McGill University Health Centre, Montréal, Québec, H3A 1A1 Canada [D. L., K. Y. L., Y. K., V. G.] and Department of Biochemistry, Medicine and Oncology, McGill University, Montréal, Québec, H3G 1Y6 Canada [V. G.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, ß, and 
are orphan nuclear hormone receptors that share significant homology with the estrogen receptors (ERs) but are not activated by natural estrogens. In contrast, the ERRs display constitutive transcriptional activity in the absence of exogenously added ligand. However, the ERRs bind to the estrogen response element and to the extended half-sites of which a subset can also be recognized by ER, suggesting that ERRs and ERs may control overlapping regulatory pathways. To test this hypothesis, we explored the possibility that ERRs could regulate the expression of the estrogen-inducible pS2 gene, a human breast cancer prognostic marker. Transfection studies show that all of the ERR isoforms can activate the pS2 promoter in a variety of cell types, including breast cancer cell lines. Surprisingly, sequence analysis combined with mutational studies revealed that, in addition to the well-characterized estrogen response element, the presence of a functional extended half-site within the pS2 promoter is also required for complete response to both ER and ERR pathways. We show that ERR transcriptional activity on the pS2 promoter is considerably enhanced in the presence of all three members of the steroid receptor coactivator family but is completely abolished on treatment with the synthetic estrogen diethylstilbestrol, a recently described inhibitor of ERR function. Finally, we demonstrate that ERR is the major isoform expressed in human breast cancer cell lines and that diethylstilbestrol can inhibit the growth of both ER-positive and -negative cell lines. Taken together, these results demonstrate that estrogen-inducible genes such as pS2 can be ERR targets and suggest that pharmacological modulation of ERR activity may have therapeutic value in the treatment of breast cancer. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and ß) that are members of the superfamily of nuclear receptors (reviewed in Ref. 2
). ER and ß, either as homodimers or heterodimers, regulate gene transcription through binding to short sequences within the promoter of target genes, referred to as EREs, that are composed of inverted repeats of the core half-site motif AGGTCA (3, 4, 5, 6)
. On estrogen binding, ER and ß acquire the ability to interact with members of the family of SRC proteins through conformational changes of the receptors (7
, 8)
. Coactivator/receptor interactions can be abrogated by antiestrogens, a mechanism that contributes to their therapeutic effect in the treatment of breast cancer. However, breast cancer often progresses from hormone dependence to hormone independence, which limits the use of tamoxifen and toremifene, the only antiestrogens currently approved for the treatment of breast cancer (9)
. This biological phenomenon is complex and involves both genetic and epigenetic changes in breast cancer cells and remains, for the most part, unresolved.
The ERRs , ß, and are orphan members of the superfamily of nuclear receptors (10, 11, 12, 13)
. Despite being most closely related to ER and ß, the ERRs are not activated by known natural estrogens but rather display constitutive transcriptional activity that appears to be isoform-, cell context-, and promoter-dependent (10
, 12
, 14, 15, 16, 17)
. However, like the ERs, the ERRs recognize the ERE, suggesting that these receptors may control overlapping regulatory pathways (18)
. In addition, ERRs bind to extended half-sites with the consensus sequence TCAAGGTCA referred to as an ERRE (16
, 17
, 19, 20, 21)
. ER but not ERß has recently been shown to recognize a subset of ERRE and stimulate the transcriptional activity of promoters containing such sites, reinforcing the concept that the two classes of related receptors share common target genes (22)
. Moreover, our laboratory has recently discovered that the synthetic estrogen DES can act as an inverse agonist or antagonist on all three of the ERR isoforms, leading to the dissociation of coactivator proteins and loss of transcriptional activation function (23)
. Taken together, these findings indicate a closer functional kinship between the two receptor subclasses than originally anticipated. Consequently, we have begun to investigate whether the ERRs may participate in classical ER-mediated pathways involved in the initiation and progression of breast cancer. Here, we demonstrate that the orphan nuclear receptors ERR, ß, and can regulate the transcriptional activity of the human breast cancer marker gene pS2 and, unexpectedly, that the full transcriptional activity of the ERs and the ERRs on the pS2 gene is dependent on the presence of an ERRE unidentified previously within its promoter. We also show that the transcriptional activity of ERRs on the pS2 gene can be abrogated by DES, suggesting that ERR, the major isoform expressed in breast cancer cell lines, may constitute a therapeutic target in the treatment of breast cancer.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Plasmids.
Reporter plasmids pS2Luc and pS2
ERELuc have been described previously (24)
. pS2ERRELuc was generated by PCR mutagenesis using PFU polymerase. A PstI/XhoI fragment containing mutated ERRE was sequenced and subcloned back into the template plasmid to eliminate the presence of undesired mutations during the amplification procedure. The oligonucleotide used was: pERRE, 5'-GAGTAGGACCTGGATTAATTCCAGGTTGGAGGAGACTCCC-3' (changes are underlined). For the construction of the pS2ERE/ERRELuc double mutant, the plasmid pS2ERRE was digested with PstI and XhoI, and the fragment containing the ERRE mutation was subcloned into the corresponding sites of pS2ERELuc. The pCMXhSRC-1 expression vector, pCMXhER, pCMXmERR, and pCMXßgal have been described (16
, 24)
. To construct pCMXrERRß, a 1.7-kb EcoRI/BamHI fragment of the HH3 cDNA (10)
containing the entire coding sequence of rat ERRß was subcloned into pCMX (25)
. To construct pCMXmERR, a 2.5-kb murine cDNA encoding the entire coding region of ERR isolated by screening a kidney cDNA library with a human expressed sequence tag clone ERR was digested with XbaI and SalI, end-filled with Klenow, and subcloned into the EcoRV site of pCMX. The VP16-mERR, VP16-rERRß, and VP16-mERR expression vectors were constructed by amplifying the entire coding region of each cDNA and subcloning the resulting blunt-ended fragment into pCMX-VP16, which had been digested previously with BamHI and subsequently blunt-ended with Klenow (gift from G. B. Tremblay, Signalgene, Montréal, Canada). All of the constructs were sequenced to confirm their integrity.
Cell Culture and Transfection.
HeLa, Cos-1, and human breast cancer cell lines ZR75.1, MDA-MB-231, HS587T, BT549, SKBr3, T47D, MCF-7, MDA-MB-448, and BT474 were maintained in DMEM supplemented with 10% FBS and 100 µg/ml penicillin and 100 µg/ml streptomycin. MCF-10a and MCF-12 cells were grown in DMEM:F12HAM (Life Technologies, Inc., Gaithersburg, MD) supplemented with 5% FBS, 100 µg/ml penicillin, and 100 µg/ml streptomycin. BT20 cells were grown in -MEM (Life Technologies, Inc.) supplemented with 5% FBS, 100 µg/ml penicillin, and 100 µg/ml streptomycin. MDA-MB-435S and MDA-MB-436 cells were grown in Leibovitz L15 (Life Technologies, Inc.) supplemented with 5% FBS, 100 µg/ml penicillin, and 100 µg/ml streptomycin. For transfection, cells were grown in phenol red-free DMEM (Life Technologies, Inc.) with 10% charcoal dextran-treated FBS for 
24 h before transfection. Cells were maintained in a humidified atmosphere at 37°C and 5% CO2. Transient transfections were performed in 12-well plates. At 
50% confluence, cells were transfected using the FuGene transfection reagent (Roche Diagnostics GmbH, Mannheim, Germany) according to the manufacturer’s instruction, typically with 0.5 µg of reporter plasmid, 0.1–0.2 µg of control plasmid pCMXßgal, 50–400 ng ER or ERR expression plasmids, and carrier DNA pBluescriptKSII for a total of 1 µg/well. After 16 h, the cells were washed and given fresh medium that contained 10% charcoal dextran-treated FBS with 10 nM E2 or 10 µM DES for 24 h. For luciferase assays, cells were lysed in 0.1 M potassium phosphate buffer pH 7.8 containing 1% Triton X-100, and light emission was detected in the presence of luciferin using a microtiter plate luminometer (Dynex Technologies, Chantilly, VA). Luciferase values were normalized for variations in transfection efficiency using the ß-galactosidase internal control and expressed as RLUs. The values for luciferase activity presented in this study as RLUs or fold induction over control represent means of a minimum of three independent transfections performed in duplicate.
For cell proliferation assays in the presence of DES and E2, MCF-7 and MDA-MB-231 cells were seeded in 96-well plates at a density of 10,000 cells/100 µl/well in phenol red-free DMEM containing 2% charcoal dextran-treated FBS. One day later and at days 3 and 6, cells were treated with ethanol or estrogens as indicated. At 3, 6, and 9 days after initiation of the treatment, a colorimetric proliferation assay was performed using the CellTiter 96 AQueous nonradioactive cell proliferation assay as directed by the manufacturer (Promega, Madison, WI).
EMSA.
In vitro translated ERR, ERRß, and ERR were generated from plasmids pCMXmERR, pCMXrERRß, and pCMXmERR using the TNT reticulocyte lysate kit (Promega). For preparation of probes, sense and antisense strands of oligonucleotides were annealed and radiolabeled by end filing with Klenow. Aliquots (5 µl) of in vitro translated proteins were preincubated in binding buffer [10 mM Tris-HCl (pH 8.0), 40 mM KCl, 10% glycerol, 1 mM DTT, and 0.05% NP40] containing 2 µg of poly (dI-dC)2, 0.1 µg of denatured salmon sperm DNA, and 10 µg of BSA for 20 min on ice. Probe (40,000 cpm) was added and allowed to bind for 20 min at room temperature. Complexes were resolved on a 5% polyacrylamide gel in 0.5 x Tris borate-EDTA and electrophoresed at 150 V at room temperature. Competition experiments were performed by adding the indicated amounts of unlabeled oligonucleotides to the reaction before adding the probe. The following oligonucleotides and their complements were used as probes: pS2-ERE, 5'-TCGACCCTGCAAGGTCACGGTGGCCACCCCGTG-3'; and pS2-ERRE, 5'-TCGACACCTGGATTAAGGTCAGGTTGGAG-3'.
Semiquantitative RT-PCR of pS2 Expression.
MDA-MB-231 cells were grown in phenol red-free DMEM (Life Technologies, Inc.) with 10% charcoal dextran-treated FBS for 24 h before transfection. Cells were transiently transfected with 5 µg of expression plasmids using FuGene transfection reagent as described above in 50 x 10-mm plates. After 16 h, the cells were washed and given fresh medium that contained 10% charcoal dextran-treated FBS with either 100 nM E2 or an ethanol vehicle for 24 h. Total RNA was extracted from transfected cells using Trizol reagent (Life Technologies, Inc.) according to the manufacturer’s protocol. The cDNA was synthesized from 2 µg of total RNA using Superscript reverse transcriptase (Life Technologies, Inc.) and oligo(dT) according to manufacturer’s instructions. The 252-bp pS2 fragment was amplified with the following primers: pS2 sense, 5'-ATGGCCACCATGGAGAACAAGG-3'; and pS2 antisense, 5'-CTAAAATTCACACTCCTCTTCTGG-3'. The amplification of a 534-bp human acidic ribosomal phosphoprotein 36B4 cDNA fragment was used as an internal PCR control. The primer pair used was: 36B4 sense, 5'-TGTTTCATTGTGGGAGCAGAC-3'; and 36B4 antisense, 5'-AAGCACTTCAGGGTTGTAGAT-3'. The reaction mixtures (50 µl) were subjected to 25, 30, and 35 amplification cycles of 45 s at 94°C, 60 s at 58°C, and 90 s at 72°C to determine the linearity of the PCR reaction. Aliquots (7 µl) of the PCR reactions taken at 30 amplification cycles were then analyzed by electrophoresis in a 1.2% agarose gel. Quantification of the electrophoresis data were performed using the ImageQuant software from images obtained with a Typhoon phosphorimager apparatus (Pharmacia Biotech, Piscataway, NJ). Two distinct transfection experiments were performed, and pS2 expression was analyzed each time by two separate RT-PCR analyses to ensure reproducibility.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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; Ref. 27
). Thus, the pS2 gene also represents a potential target for members of the ERR family. We first tested whether the three ERR isoforms could activate the pS2 promoter when transfected in HeLa cells, an ER-negative cell line originally used for the characterization of the pS2 promoter (28)
. As expected, ER induces a 12-fold stimulation of the activity of the pS2 luciferase reporter in a E2-dependent manner (Fig. 1B)
. In contrast, two of the ERR isoforms, ERRß and , constitutively stimulate by 4-fold the activity of the pS2 promoter (Fig. 1B)
, and the presence of E2 had no effect on their activity. The lack of constitutive ERR transcriptional activity is in agreement with previous studies from our laboratory (16)
. However, VP16-mERR as well as VP16-rERRß and VP16-mERR chimeras, constructs that allow evaluation of receptor-promoter interactions in the absence of potential ligands or cell-specific cofactors, increase transactivation of the pS2 reporter above the level achieved with ER in the presence of E2 (Fig. 1C)
. Taken together, these results demonstrate that the pS2 promoter can be considered a valid target of all three members of the ERR family.
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ERE; Fig. 2A
). As expected, the pS2ERE reporter failed to respond to ER in the presence of E2 (Fig. 2B)
. Surprisingly, the pS2ERE reporter was still significantly responsive to the presence of ERRß and , albeit at a lower level than that observed with the intact reporter. This observation was even more striking when transcriptional activity was assessed using the VP16-ERR chimeras (Fig. 2C)
. All three of the VP16-ERR chimeras generated between 5- and 8-fold induction of the luciferase activity from the mutant pS2 promoter. These results indicate that whereas the pS2 promoter is a direct target of the ERR isoforms and that the ERE participates in that response, the presence of additional response element(s) appears to be necessary to generate a full response from the ERR isoforms.
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binding site TNAAGGTCA as defined previously by selected and amplified binding analysis (Fig. 3B
; Ref. 16
). To test whether the ERR isoforms can interact with the pS2 ERE and this newly identified element, we preformed EMSA using in vitro-synthesized ERR, ß, and and synthetic 32P-labeled oligonucleotides representing the pS2 ERE, as well as the putative ERRE. As shown in Fig. 3C
, all three of the ERR isoforms bind to the pS2 ERE, and the binding is specifically competed by addition of increasing amounts of unlabeled synthetic ERE oligonucleotides. Similarly, the ERR isoforms bind to the pS2 ERRE, and in each case binding is competed by unlabeled ERRE oligonucleotides.
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. Mutation of the ERRE resulted in more than a 60% decrease in ERRß- and ERR-dependent transcriptional activity, whereas mutation of both elements completely abolished the ERR-mediated response (Fig. 4B)
. The requirement of the ERRE for the ERR-mediated response is even more striking in the presence of the VP16-ERR chimeras (Fig. 4C)
. In this assay, the ERR responses were diminished by up to 80% in the absence of a functional ERRE and completely lost when both ERRE and ERE were mutated. We also observed that mutation of the ERRE resulted in a 50% diminution of the E2 response mediated by transfected ER, suggesting that the pS2 ERRE is also a functional ER response element.
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, the three ERR isoforms, or the VP16-ERR chimeras. As shown in Fig. 5
, ER elicited an E2 response in all three of the cell lines. Note that the lack of response to E2 in the ER-positive cell line ZR75.1 in the absence of transfected ER is consistent with previous studies that showed that an episomal pS2 promoter is unresponsive to endogenous ER (28)
. In agreement with data obtained in HeLa cells, ERR did not stimulate the activity of the pS2 promoter in all three of the human breast cancer cell lines. However, both ERRß and induced transcription from the pS2 promoter by 3-fold in ZR75.1 and MDA-MB-231 cells and up to 10-fold in HS578T cells. In contrast, all three of the VP16-ERR chimeras generated a strong transcriptional response from the pS2 promoter. However, the level of response varied in the three of the cell lines, especially in comparison with the response observed with ER in the presence of E2.
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25%) of MDA-MB-231 cells and expressed ER; ERR, ß, and ; or the three VP16-ERR chimeras. Semiquantitative RT-PCR analysis demonstrated that transiently transfected ER can induce the expression of the pS2 gene in an E2-dependent manner (Fig. 6
, Lanes 3 and 4). As observed previously with the pS2 luciferase reporter, ERR did not influence pS2 transcription in this assay. However, significant activation of pS2 expression was observed on transfection with ERRß and ERR expression vectors (Fig. 5
, Lanes 6 and 7). On the other hand, all three of the VP16-ERR chimeras elicited a strong transcriptional response from the endogenous pS2 gene (Fig. 6
, Lanes 8 to 10). These results, which parallel the data obtained with the pS2 luciferase reporter, clearly demonstrate that the ERR isoforms possess the potential to regulate the expression of the pS2 gene in the context of its own genomic regulatory environment.
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(Fig. 7)
. The transcriptional activity of ERRß was also enhanced by all three of the coactivators. In contrast, ERR did not respond to the presence of SRC-1, whereas both GRIP-1 and pCIP allowed a stronger transcriptional response from ERR. These experiments show that the transcriptional activity of ERR isoforms is dependent on the presence of specific coactivators.
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, DES completely abolished basal or GRIP-1-stimulated ERR responses on the pS2 promoter.
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Is Expressed in Breast Cancer Cell Lines.
, expression of ERR was detected in all of the human beast cancer cell lines as well as the normal mammary epithelial MCF-10a and MCF-12 cell lines. The expression of ERRß and was not detected using that technique.
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, both DES and E2 at 10 nM stimulated MCF-7 cell proliferation but, as expected, had no effect on MDA-MB-231 cell proliferation. In contrast, when used at 3 µM, DES but not E2 inhibited the proliferation of both cell lines suggesting the existence of a DES-dependent ER-independent mechanism for this effect.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-mediated response places the ERRs at an unique position in the control of estrogenic signaling pathways and reinforces the notion that these orphan nuclear receptors may play a more important role than anticipated previously in estrogen physiology (22)
. Whereas the ER and ERR isoforms share a highly conserved DNA binding domain, a property that allows for the recognition of common response elements and the ability to regulate common target genes, important functional differences also exist between members of the two subfamilies and receptor isoforms. ER and ß are inactive in the absence of hormonal signal, whereas ERR isoforms display significant constitutive transcriptional activity as both repressors and activators (2
, 12
, 14, 15, 16, 17
, 23
, 29
, 31)
. In particular, the activity of the ERR isoforms as activators or repressors appears to be dependent on the relative level of coactivator proteins and culture conditions when assayed in transient transfection experiments. Therefore, it is difficult at present to precisely delineate the exact role played by the ERR isoforms in pS2 expression.
Our expression study suggests that ERR is the major isoform expressed in breast cancer cell lines (Fig. 9)
. ERR transcriptional activity is particularly low in the absence of coactivator protein and could therefore interfere with ER signaling. On the other hand, ERR activity has been found to be stimulated by a charcoal treatment-removable compound present in specific batches of sera (14)
, suggesting that ERR may exert a ligand-dependent positive influence on pS2 expression in a more relevant physiological context. In addition, a significant number of human breast tumors display amplification of the AIB1/pCIP coactivator gene (32
, 33) , which could contribute to the enhancement of ERR activity in cancer cells. Taken together, these observations suggest that ERR could play an important role in regulating estrogenic pathways in breast tumors. Therefore, it will be crucial to assess the relative levels of expression of ERR isoforms and coactivator proteins during breast cancer progression, especially during the transition from a hormone-dependent to a hormone-independent status. In addition, we have detected expression of both ERR and ERRß isoforms during all stages of mammary gland development in the mouse,4
suggesting that both isoforms may play a role in mammary gland physiology.
We have recently demonstrated that the transcriptional activity of ERRs and ERs can be controlled by at least one common synthetic ligand, DES, which indicates that their ligand-binding pockets share common functional determinants (23)
. More importantly is the demonstration that DES has opposite action on ERs and ERRs: agonistic on ERs and antagonistic on ERRs. It is well known that treatment with pharmacological doses of DES is as effective as tamoxifen therapy for the treatment of breast cancer but that the substantial incidence of side effects prevents a wide usage of DES in a clinical setting (34, 35, 36)
. However, no clear biological explanation and molecular mechanism have been provided for the inhibitory action of DES on breast cancer cell proliferation and the role that the ERs might play in that process (30
, 37)
. The observation that the constitutive activity of the ERR isoforms on the pS2 gene can be abrogated by DES (Fig. 8)
suggests that the inhibitory action of DES on ERR transcriptional activity may be an element of its therapeutic efficacy. The demonstration that DES can inhibit the proliferation of both ER-positive and ER-negative cells also support this concept (Fig. 10
and Ref. 30
). Whereas future investigations with ERR-specific inhibitors will be necessary to validate this hypothesis, the observation that ERR is expressed in breast cancer cell lines and control a marker gene linked to the estrogenic signaling pathway and that a therapeutically relevant ligand down-regulates this activity opens new research avenues on the role of ERR and its potential ligands in breast cancer etiology and treatment.
The orphan nuclear receptors ERR, ß, and and the classic nuclear receptors ER and ß can now be considered, functionally, as an extended family. These receptors share common target genes (this study and Ref. 22
) and a pharmacologically relevant synthetic ligand (23)
. These findings indicate that careful consideration should be given to all members of this extended family of nuclear receptors when physiological and pathological pathways linked to estrogens are being investigated. The identification of a natural hormone associated with ERR signaling and/or the development of specific ERR ligands, combined with the use of genetic models with null alleles of ER and ERR genes and functional genomics tools, will be essential to assign precise functions to each receptor isoform and to evaluate the extent of transcriptional cross-talk between the two receptor subfamilies.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by the Canadian Breast Cancer Research Initiative. V. G. is a Senior Scientist of the Canadian Institutes for Health Research. 
2 To whom request for reprints should be addressed, at Molecular Oncology Group, McGill University Health Center, 687 Pine Avenue West, Montréal, Québec, H3A 1A1 Canada. Phone: (514) 843-1479; Fax: (514) 843-1478; E-mail: vgiguere{at}dir.molonc.mcgill.ca
3 The abbreviations used are: ER, estrogen receptor; ERR, estrogen-receptor-related receptor; ERE, estrogen response element; ERRE, estrogen related response element; SRC, steroid receptor coactivator; DES, diethylstilbestrol; E2, estradiol; RLU, relative luciferase unit; EMSA, electrophoretic mobility shift assay; RT-PCR, reverse transcription-PCR.
4 G. Charhour and V. Giguère, unpublished observation.
Received 3/16/01. Accepted 7/13/01.
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REFERENCES |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and ß form heterodimers on DNA. J. Biol. Chem., 272: 19858-19862, 1997.. Mol. Endocrinol., 11: 1486-1496, 1997.-ß heterodimer complex. Mol. Cell. Biol., 19: 1919-1927, 1999. (estrogen receptor-related receptor-). Mol. Endocrinol., 13: 764-773, 1999. is a transcriptional regulator of the human medium-chain acyl coenzyme A dehydrogenase gene. Mol. Cell. Biol., 17: 5400-5409, 1997.[Abstract]
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D. Nichol, M. Christian, J. H. Steel, R. White, and M. G. Parker RIP140 Expression Is Stimulated by Estrogen-related Receptor {alpha} during Adipogenesis J. Biol. Chem., October 27, 2006; 281(43): 32140 - 32147. [Abstract] [Full Text] [PDF]
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 M. L. King, S. R. Adler, and L. L. Murphy Extraction-Dependent Effects of American Ginseng (Panax quinquefolium) on Human Breast Cancer Cell Proliferation and Estrogen Receptor Activation Integr Cancer Ther, September 1, 2006; 5(3): 236 - 243. [Abstract] [PDF]
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A. Castet, A. Herledan, S. Bonnet, S. Jalaguier, J.-M. Vanacker, and V. Cavailles Receptor-Interacting Protein 140 Differentially Regulates Estrogen Receptor-Related Receptor Transactivation Depending on Target Genes Mol. Endocrinol., May 1, 2006; 20(5): 1035 - 1047. [Abstract] [Full Text] [PDF]
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 A. Watanabe, Y. Kinoshita, K. Hosokawa, T. Mori, T. Yamaguchi, and H. Honjo Function of Estrogen-Related Receptor {alpha} in Human Endometrial Cancer J. Clin. Endocrinol. Metab., April 1, 2006; 91(4): 1573 - 1577. [Abstract] [Full Text] [PDF]
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P. A. McChesney, S. E. Aiyar, O.-J. Lee, A. Zaika, C. Moskaluk, R. Li, and W. El-Rifai Cofactor of BRCA1: A Novel Transcription Factor Regulator in Upper Gastrointestinal Adenocarcinomas Cancer Res., February 1, 2006; 66(3): 1346 - 1353. [Abstract] [Full Text] [PDF]
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J. B. Barry, J. Laganiere, and V. Giguere A Single Nucleotide in an Estrogen-Related Receptor {alpha} Site Can Dictate Mode of Binding and Peroxisome Proliferator-Activated Receptor {gamma} Coactivator 1{alpha} Activation of Target Promoters Mol. Endocrinol., February 1, 2006; 20(2): 302 - 310. [Abstract] [Full Text] [PDF]
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W. Zhou, Z. Liu, J. Wu, J.-h. Liu, S. M. Hyder, E. Antoniou, and D. B. Lubahn Identification and Characterization of Two Novel Splicing Isoforms of Human Estrogen-Related Receptor {beta} J. Clin. Endocrinol. Metab., February 1, 2006; 91(2): 569 - 579. [Abstract] [Full Text] [PDF]
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 D. Lu, H. B. Cottam, M. Corr, and D. A. Carson Repression of {beta}-catenin function in malignant cells by nonsteroidal antiinflammatory drugs PNAS, December 20, 2005; 102(51): 18567 - 18571. [Abstract] [Full Text] [PDF]
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Y.-Y. Park, S.-W. Ahn, H.-J. Kim, J.-M. Kim, I.-K. Lee, H. Kang, and H.-S. Choi An autoregulatory loop controlling orphan nuclear receptor DAX-1 gene expression by orphan nuclear receptor ERR{gamma} Nucleic Acids Res., November 28, 2005; 33(21): 6756 - 6768. [Abstract] [Full Text] [PDF]
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J. Laganiere, G. Deblois, C. Lefebvre, A. R. Bataille, F. Robert, and V. Giguere From the Cover: Location analysis of estrogen receptor {alpha} target promoters reveals that FOXA1 defines a domain of the estrogen response PNAS, August 16, 2005; 102(33): 11651 - 11656. [Abstract] [Full Text] [PDF]
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J. Seely, K. S. Amigh, T. Suzuki, B. Mayhew, H. Sasano, V. Giguere, J. Laganiere, B. R. Carr, and W. E. Rainey Transcriptional Regulation of Dehydroepiandrosterone Sulfotransferase (SULT2A1) by Estrogen-Related Receptor {alpha} Endocrinology, August 1, 2005; 146(8): 3605 - 3613. [Abstract] [Full Text] [PDF]
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J. B. Barry and V. Giguere Epidermal Growth Factor-Induced Signaling in Breast Cancer Cells Results in Selective Target Gene Activation by Orphan Nuclear Receptor Estrogen-Related Receptor {alpha} Cancer Res., July 15, 2005; 65(14): 6120 - 6129. [Abstract] [Full Text] [PDF]
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E. Bonnelye and J. E. Aubin Estrogen Receptor-Related Receptor {alpha}: A Mediator of Estrogen Response in Bone J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 3115 - 3121. [Abstract] [Full Text] [PDF]
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C. P. Cheung, S. Yu, K. B. Wong, L. W. Chan, F. M. M. Lai, X. Wang, M. Suetsugi, S. Chen, and F. L. Chan Expression and Functional Study of Estrogen Receptor-Related Receptors in Human Prostatic Cells and Tissues J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1830 - 1844. [Abstract] [Full Text] [PDF]
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J. Kallen, J.-M. Schlaeppi, F. Bitsch, I. Filipuzzi, A. Schilb, V. Riou, A. Graham, A. Strauss, M. Geiser, and B. Fournier 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} J. Biol. Chem., November 19, 2004; 279(47): 49330 - 49337. [Abstract] [Full Text] [PDF]
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 K. Stokes, B. Alston-Mills, and C. Teng Estrogen response element and the promoter context of the human and mouse lactoferrin genes influence estrogen receptor {alpha}-mediated transactivation activity in mammary gland cells J. Mol. Endocrinol., October 1, 2004; 33(2): 315 - 334. [Abstract] [Full Text] [PDF]
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B Horard, A Castet, P-L Bardet, V Laudet, V Cavailles, and J-M Vanacker Dimerization is required for transactivation by estrogen-receptor-related (ERR) orphan receptors: evidence from amphioxus ERR J. Mol. Endocrinol., October 1, 2004; 33(2): 493 - 509. [Abstract] [Full Text] [PDF]
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H. Greschik, R. Flaig, J.-P. Renaud, and D. Moras Structural Basis for the Deactivation of the Estrogen-related Receptor {gamma} by Diethylstilbestrol or 4-Hydroxytamoxifen and Determinants of Selectivity J. Biol. Chem., August 6, 2004; 279(32): 33639 - 33646. [Abstract] [Full Text] [PDF]
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T. Suzuki, Y. Miki, T. Moriya, N. Shimada, T. Ishida, H. Hirakawa, N. Ohuchi, and H. Sasano Estrogen-Related Receptor {alpha} in Human Breast Carcinoma as a Potent Prognostic Factor Cancer Res., July 1, 2004; 64(13): 4670 - 4676. [Abstract] [Full Text] [PDF]
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P. J. Willy, I. R. Murray, J. Qian, B. B. Busch, W. C. Stevens Jr., R. Martin, R. Mohan, S. Zhou, P. Ordentlich, P. Wei, et al. Regulation of PPAR{gamma} coactivator 1{alpha} (PGC-1{alpha}) signaling by an estrogen-related receptor {alpha} (ERR{alpha}) ligand PNAS, June 15, 2004; 101(24): 8912 - 8917. [Abstract] [Full Text] [PDF]
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J. Laganiere, G. B. Tremblay, C. R. Dufour, S. Giroux, F. Rousseau, and V. Giguere A Polymorphic Autoregulatory Hormone Response Element in the Human Estrogen-related Receptor {alpha} (ERR{alpha}) Promoter Dictates Peroxisome Proliferator-activated Receptor {gamma} Coactivator-1{alpha} Control of ERR{alpha} Expression J. Biol. Chem., April 30, 2004; 279(18): 18504 - 18510. [Abstract] [Full Text] [PDF]
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T. Tokumoto, M. Tokumoto, R. Horiguchi, K. Ishikawa, and Y. Nagahama Diethylstilbestrol induces fish oocyte maturation PNAS, March 9, 2004; 101(10): 3686 - 3690. [Abstract] [Full Text] [PDF]
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D. Lu, Y. Zhao, R. Tawatao, H. B. Cottam, M. Sen, L. M. Leoni, T. J. Kipps, M. Corr, and D. A. Carson Activation of the Wnt signaling pathway in chronic lymphocytic leukemia PNAS, March 2, 2004; 101(9): 3118 - 3123. [Abstract] [Full Text] [PDF]
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J. Luo, R. Sladek, J. Carrier, J.-A. Bader, D. Richard, and V. Giguere Reduced Fat Mass in Mice Lacking Orphan Nuclear Receptor Estrogen-Related Receptor {alpha} Mol. Cell. Biol., November 15, 2003; 23(22): 7947 - 7956. [Abstract] [Full Text] [PDF]
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Q. Xu and C. Lee Discovery of novel splice forms and functional analysis of cancer-specific alternative splicing in human expressed sequences Nucleic Acids Res., October 1, 2003; 31(19): 5635 - 5643. [Abstract] [Full Text] [PDF]
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M. J. Ellis, A. Coop, B. Singh, Y. Tao, A. Llombart-Cussac, F. Janicke, L. Mauriac, E. Quebe-Fehling, H. A. Chaudri-Ross, D. B. Evans, et al. Letrozole Inhibits Tumor Proliferation More Effectively than Tamoxifen Independent of HER1/2 Expression Status Cancer Res., October 1, 2003; 63(19): 6523 - 6531. [Abstract] [Full Text] [PDF]
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S. N. Schreiber, D. Knutti, K. Brogli, T. Uhlmann, and A. Kralli The Transcriptional Coactivator PGC-1 Regulates the Expression and Activity of the Orphan Nuclear Receptor Estrogen-Related Receptor alpha (ERRalpha ) J. Biol. Chem., March 7, 2003; 278(11): 9013 - 9018. [Abstract] [Full Text] [PDF]
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E. A. Ariazi, G. M. Clark, and J. E. Mertz Estrogen-related Receptor {alpha} and Estrogen-related Receptor {gamma} Associate with Unfavorable and Favorable Biomarkers, Respectively, in Human Breast Cancer Cancer Res., November 15, 2002; 62(22): 6510 - 6518. [Abstract] [Full Text] [PDF]
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J. M. Huss, R. P. Kopp, and D. P. Kelly Peroxisome Proliferator-activated Receptor Coactivator-1alpha (PGC-1alpha ) Coactivates the Cardiac-enriched Nuclear Receptors Estrogen-related Receptor-alpha and -gamma . IDENTIFICATION OF NOVEL LEUCINE-RICH INTERACTION MOTIF WITHIN PGC-1alpha J. Biol. Chem., October 18, 2002; 277(43): 40265 - 40274. [Abstract] [Full Text] [PDF]
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E. Bonnelye, V. Kung, C. Laplace, D. L. Galson, and J. E. Aubin Estrogen Receptor-Related Receptor {alpha} Impinges on the Estrogen Axis in Bone: Potential Function in Osteoporosis Endocrinology, September 1, 2002; 143(9): 3658 - 3670. [Abstract] [Full Text] [PDF]
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M. R. Fielden, R. G. Halgren, C. J. Fong, C. Staub, L. Johnson, K. Chou, and T. R. Zacharewski Gestational and Lactational Exposure of Male Mice to Diethylstilbestrol Causes Long-Term Effects on the Testis, Sperm Fertilizing Ability in Vitro, and Testicular Gene Expression Endocrinology, August 1, 2002; 143(8): 3044 - 3059. [Abstract] [Full Text] [PDF]
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R. J. Kraus, E. A. Ariazi, M. L. Farrell, and J. E. Mertz Estrogen-related Receptor alpha 1 Actively Antagonizes Estrogen Receptor-regulated Transcription in MCF-7 Mammary Cells J. Biol. Chem., June 28, 2002; 277(27): 24826 - 24834. [Abstract] [Full Text] [PDF]
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T. M. Willson and J. T. Moore Minireview: Genomics Versus Orphan Nuclear Receptors--A Half-Time Report Mol. Endocrinol., June 1, 2002; 16(6): 1135 - 1144. [Abstract] [Full Text] [PDF]
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. The TATA box sequence is underlined. B, comparison between consensus ERE and ERRE and the pS2 ERE and ERRE. C, EMSA performed with the pS2 ERE and ERRE probes. The probes were radiolabeled and incubated with in vitro-translated ERR
. B, wild-type and mutated pS2Luc reporter constructs were cotransfected into HeLa cells with expression vectors carrying ER
