This Article Full Text Full Text (PDF) All Versions of this Article: 19/6/1584    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager NURSA Molecule Pages Link Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Laganière, J. Articles by Giguère, V. Search for Related Content PubMed PubMed Citation Articles by Laganière, J. Articles by Giguère, V.

Functional Genomics Identifies a Mechanism for Estrogen Activation of the Retinoic Acid Receptor 1 Gene in Breast Cancer Cells

Molecular Oncology Group (J.L., G.D., V.G.), McGill University Health Center, and Departments of Biochemistry (J.L., V.G.), Medicine (V.G.), and Oncology (V.G.), McGill University, Montréal, Québec, Canada H3A 1A1

Address all correspondence and requests for reprints to: Dr. Vincent Giguère, Molecular Oncology Group, McGill University Health Centre, Room H5–21, 687 Pine Avenue West, Montréal, Québec, Canada H3A 1A1. E-mail: vincent.giguere{at}mcgill.ca.

The identification of estrogen receptor (ER) target genes is crucial to our understanding of its predominant role in breast cancer. In this study, we used a chromatin immunoprecipitation (ChIP)-cloning strategy to identify ER-regulatory modules and associated target genes in the human breast cancer cell line MCF-7. We isolated 12 transcriptionally active genomic modules that recruit ER and the coactivator steroid receptor coactivator (SRC)-3 to different intensities in vivo. One of the ER-regulatory modules identified is located 3.7 kb downstream of the first transcriptional start site of the RARA locus, which encodes retinoic acid receptor 1 (RAR1). This module, which includes an estrogen response element (ERE), is conserved between the human and mouse genomes. Direct binding of ER to the ERE was shown using EMSAs, and transient transfections in MCF-7 cells demonstrated that endogenous ER can induce estrogen-dependent transcriptional activation from the module or the ERE linked to a heterologous promoter. Furthermore, ChIP assays showed that the coregulators SRC-1, SRC-3, and receptor-interacting protein 140 are recruited to this intronic module in an estrogen-dependent manner. As expected from previous studies, the transcription factor Sp1 can be detected at the RARA 1 promoter by ChIP. However, treatment with estradiol did not influence Sp1 recruitment nor help recruit ER to the promoter. Finally, ablation of the intronic ERE was sufficient to abrogate the up-regulation of RARA 1 promoter activity by estradiol. Thus, this study uncovered a mechanism by which ER significantly activates RAR1 expression in breast cancer cells and exemplifies the utility of functional genomics strategies in identifying long-distance regulatory modules for nuclear receptors.

NURSA Molecule Pages Link:

Nuclear Receptors:   RARα  |  ERα

Coregulators:   RIP140  |  SRC-1  |  AIB1

Ligands:   17β-Estradiol

This article has been cited by other articles:

				G. Deblois and V. Giguere Nuclear Receptor Location Analyses in Mammalian Genomes: From Gene Regulation to Regulatory Networks Mol. Endocrinol., September 1, 2008; 22(9): 1999 - 2011. [Abstract] [Full Text] [PDF]

				X. Li, S. L Nott, Y. Huang, R. Hilf, R. A Bambara, X. Qiu, A. Yakovlev, S. Welle, and M. Muyan Gene expression profiling reveals that the regulation of estrogen-responsive element-independent genes by 17{beta}-estradiol-estrogen receptor {beta} is uncoupled from the induction of phenotypic changes in cell models J. Mol. Endocrinol., May 1, 2008; 40(5): 211 - 229. [Abstract] [Full Text] [PDF]

				A. M. Tremblay, B. J. Wilson, X.-J. Yang, and V. Giguere Phosphorylation-Dependent Sumoylation Regulates Estrogen-Related Receptor-{alpha} and -{gamma} Transcriptional Activity through a Synergy Control Motif Mol. Endocrinol., March 1, 2008; 22(3): 570 - 584. [Abstract] [Full Text] [PDF]

				N. Levy, D. Tatomer, C. B. Herber, X. Zhao, H. Tang, T. Sargeant, L. J. Ball, J. Summers, T. P. Speed, and D. C. Leitman Differential Regulation of Native Estrogen Receptor-Regulatory Elements by Estradiol, Tamoxifen, and Raloxifene Mol. Endocrinol., February 1, 2008; 22(2): 287 - 303. [Abstract] [Full Text] [PDF]

				J. Sun, Z. Nawaz, and J. M. Slingerland Long-Range Activation of GREB1 by Estrogen Receptor via Three Distal Consensus Estrogen-Responsive Elements in Breast Cancer Cells Mol. Endocrinol., November 1, 2007; 21(11): 2651 - 2662. [Abstract] [Full Text] [PDF]

				P. A. Madureira, R. Varshochi, D. Constantinidou, R. E. Francis, R. C. Coombes, K.-M. Yao, and E. W.-F. Lam The Forkhead Box M1 Protein Regulates the Transcription of the Estrogen Receptor {alpha} in Breast Cancer Cells J. Biol. Chem., September 1, 2006; 281(35): 25167 - 25176. [Abstract] [Full Text] [PDF]

				J. S. Carroll and M. Brown Estrogen Receptor Target Gene: An Evolving Concept Mol. Endocrinol., August 1, 2006; 20(8): 1707 - 1714. [Abstract] [Full Text] [PDF]

				A. E. Gururaj, R. R. Singh, S. K. Rayala, C. Holm, P. den Hollander, H. Zhang, S. Balasenthil, A. H. Talukder, G. Landberg, and R. Kumar MTA1, a transcriptional activator of breast cancer amplified sequence 3 PNAS, April 25, 2006; 103(17): 6670 - 6675. [Abstract] [Full Text] [PDF]

				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]