Estrogen-related Receptor α1 Actively Antagonizes Estrogen Receptor-regulated Transcription in MCF-7 Mammary Cells*

The estrogen-related receptor α (ERRα) is an orphan member of the nuclear receptor superfamily. We show that the major isoform of the human ERRα gene, ERRα1, can sequence-specifically bind a consensus palindromic estrogen response element (ERE) and directly compete with estrogen receptor α (ERα) for binding. ERRα1 activates or represses ERE-regulated transcription in a cell type-dependent manner, repressing in ER-positive MCF-7 cells while activating in ER-negative HeLa cells. Thus, ERRα1 can function both as a modulator of estrogen responsiveness and as an estrogen-independent activator. Repression likely occurs in the absence of exogenous ligand since charcoal treatment of the serum had no effect on silencing activity. Mutational analysis revealed that repression is not simply the result of competition between ERα and ERRα1 for binding to the DNA. Rather, it also requires the presence of sequences within the carboxyl-terminal E/F domain of ERRα1. Thus, ERRα1 can function as either an active repressor or a constitutive activator of ERE-dependent transcription. We hypothesize that ERRα1 can play a critical role in the etiology of some breast cancers, thereby providing a novel therapeutic target in their treatment.

[1]  Zhiping Zhang,et al.  Estrogen receptor α and estrogen receptor-related receptor α1 compete for binding and coactivator , 2001, Molecular and Cellular Endocrinology.

[2]  R. Kraus,et al.  Identification of a Novel Element Involved in Regulation of the Lytic Switch BZLF1 Gene Promoter of Epstein-Barr Virus , 2001, Journal of Virology.

[3]  C. Yang,et al.  Two organochlorine pesticides, toxaphene and chlordane, are antagonists for estrogen-related receptor alpha-1 orphan receptor. , 1999, Cancer research.

[4]  K. Lee,et al.  Transcriptional regulation of the estrogen-inducible pS2 breast cancer marker gene by the ERR family of orphan nuclear receptors. , 2001, Cancer research.

[5]  R. Simon,et al.  Estrogen receptor status: an important variable in predicting response to endocrine therapy in metastatic breast cancer. , 1980, European journal of cancer.

[6]  C. Teng,et al.  The mouse estrogen receptor-related orphan receptor alpha 1: molecular cloning and estrogen responsiveness. , 1997, Journal of molecular endocrinology.

[7]  B. O’Malley,et al.  Molecular mechanisms of action of steroid/thyroid receptor superfamily members. , 1994, Annual review of biochemistry.

[8]  A. Cooney,et al.  Repression of estrogen-dependent stimulation of the oxytocin gene by chicken ovalbumin upstream promoter transcription factor I. , 1994, The Journal of biological chemistry.

[9]  J. Lehmann,et al.  4-Hydroxytamoxifen binds to and deactivates the estrogen-related receptor γ , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[10]  V. Laudet,et al.  Activation of the osteopontin promoter by the orphan nuclear receptor estrogen receptor related alpha. , 1998, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[11]  B. Katzenellenbogen,et al.  Differential DNA-binding abilities of estrogen receptor occupied with two classes of antiestrogens: studies using human estrogen receptor overexpressed in mammalian cells. , 1991, Nucleic acids research.

[12]  R. Evans,et al.  Identification of a new class of steroid hormone receptors , 1988, Nature.

[13]  J. Lehmann,et al.  Orphan nuclear receptors: shifting endocrinology into reverse. , 1999, Science.

[14]  J. Gustafsson,et al.  Transcriptional targets shared by estrogen receptor‐related receptors (ERRs) and estrogen receptor (ER) α, but not by ERβ , 1999 .

[15]  Shiuan Chen,et al.  Modulation of Aromatase Expression in the Breast Tissue by ERRα-1 Orphan Receptor , 1998 .

[16]  Gene regulation by steroid hormones , 1989, Cell.

[17]  V. Laudet,et al.  Expression of the estrogen-related receptor 1 (ERR-1) orphan receptor during mouse development , 1997, Mechanisms of Development.

[18]  G. Jenster.  Coactivators and corepressors as mediators of nuclear receptor function: An update , 1998, Molecular and Cellular Endocrinology.

[19]  T. Mcdonald,et al.  Identification of two hERR2-related novel nuclear receptors utilizing bioinformatics and inverse PCR. , 1999, Gene.

[20]  Miguel Beato,et al.  Steroid hormone receptors: Many Actors in search of a plot , 1995, Cell.

[21]  M. Beato,et al.  Steroid hormone receptors: interaction with deoxyribonucleic acid and transcription factors. , 1993, Endocrine reviews.

[22]  J. Katzenellenbogen,et al.  Photoaffinity labels for estrogen binding proteins of rat uterus. , 1973, Biochemistry.

[23]  R. Kraus,et al.  SV40 early-to-late switch involves titration of cellular transcriptional repressors. , 1993, Genes & development.

[24]  R. Kraus,et al.  Nuclear factor 1 family members mediate repression of the BK virus late promoter. , 2001, Virology.

[25]  V. Giguère,et al.  The orphan nuclear receptor estrogen-related receptor alpha is a transcriptional regulator of the human medium-chain acyl coenzyme A dehydrogenase gene , 1997, Molecular and cellular biology.

[26]  Rick B. Vega,et al.  A Role for Estrogen-related Receptor α in the Control of Mitochondrial Fatty Acid β-Oxidation during Brown Adipocyte Differentiation* , 1997, The Journal of Biological Chemistry.

[27]  R. Evans,et al.  Orphan nuclear receptors--new ligands and new possibilities. , 1998, Genes & Development.

[28]  E. J. Gregory,et al.  Estrogen receptor as an independent prognostic factor for early recurrence in breast cancer. , 1977, Cancer research.

[29]  C. Glass,et al.  Co-activators and co-repressors in the integration of transcriptional responses. , 1998, Current opinion in cell biology.

[30]  C. Teng,et al.  Estrogen Receptor-related Receptor α1 Interacts with Coactivator and Constitutively Activates the Estrogen Response Elements of the Human Lactoferrin Gene* , 2000, The Journal of Biological Chemistry.

[31]  R. Evans,et al.  Nuclear Receptors in Sicily: All in the Famiglia , 1997, Cell.

[32]  J. Blenis,et al.  pp90rsk1 Regulates Estrogen Receptor-Mediated Transcription through Phosphorylation of Ser-167 , 1998, Molecular and Cellular Biology.

[33]  D. Lannigan,et al.  Estradiol-induced Phosphorylation of Serine 118 in the Estrogen Receptor Is Independent of p42/p44 Mitogen-activated Protein Kinase* , 1998, The Journal of Biological Chemistry.

[34]  D. Picard,et al.  Activation of the unliganded estrogen receptor by EGF involves the MAP kinase pathway and direct phosphorylation. , 1996, The EMBO journal.

[35]  V. Jordan,et al.  Increasing the number of tandem estrogen response elements increases the estrogenic activity of a tamoxifen analogue. , 1995, Cancer letters.

[36]  H. Li,et al.  Coactivation and corepression in transcriptional regulation by steroid/nuclear hormone receptors. , 1998, Critical reviews in eukaryotic gene expression.

[37]  R. Evans,et al.  The steroid and thyroid hormone receptor superfamily. , 1988, Science.

[38]  M. Stallcup,et al.  Hormone-independent Transcriptional Activation and Coactivator Binding by Novel Orphan Nuclear Receptor ERR3* , 1999, The Journal of Biological Chemistry.

[39]  J. Rossant,et al.  Diethylstilbestrol regulates trophoblast stem cell differentiation as a ligand of orphan nuclear receptor ERR beta. , 2001, Genes & development.

[40]  C. Teng,et al.  Estrogen-related Receptor, hERR1, Modulates Estrogen Receptor-mediated Response of Human Lactoferrin Gene Promoter (*) , 1996, The Journal of Biological Chemistry.

[41]  K. Umesono,et al.  The nuclear receptor superfamily: The second decade , 1995, Cell.

[42]  Daniel Metzger,et al.  Activation of the Estrogen Receptor Through Phosphorylation by Mitogen-Activated Protein Kinase , 1995, Science.