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Department of Molecular and Integrative Physiology, University of Illinois (J.F., J.M.D., B.S.K.), Urbana, Illinois 61801; and Womens Health Research Institute, Wyeth Research (B.K., K.C.N.C., C.R.L.), Collegeville, Pennsylvania 19426
Address all correspondence and requests for reprints to: Dr. Benita S. Katzenellenbogen, Department of Molecular and Integrative Physiology, University of Illinois, 524 Burrill Hall, 407 South Goodwin Avenue, Urbana, Illinois 61801-3704. E-mail: katzenel{at}life.uiuc.edu.
Estrogens are known to regulate the proliferation of breast cancer cells and to alter their cytoarchitectural and phenotypic properties, but the gene networks and pathways by which estrogenic hormones regulate these events are only partially understood. We used global gene expression profiling by Affymetrix GeneChip microarray analysis, with quantitative PCR verification in many cases, to identify patterns and time courses of genes that are either stimulated or inhibited by estradiol (E2) in estrogen receptor (ER)-positive MCF-7 human breast cancer cells. Of the >12,000 genes queried, over 400 showed a robust pattern of regulation, and, notably, the majority (70%) were down-regulated. We observed a general up-regulation of positive proliferation regulators, including survivin, multiple growth factors, genes involved in cell cycle progression, and regulatory factor-receptor loops, and the down-regulation of transcriptional repressors, such as Mad4 and JunB, and of antiproliferative and proapoptotic genes, including B cell translocation gene-1 and -2, cyclin G2, BCL-2 antagonist/killer 1, BCL 2-interacting killer, caspase 9, and TGFß family growth inhibitory factors. These together likely contribute to the stimulation of proliferation and the suppression of apoptosis by E2 in these cells. Of interest, E2 appeared to modulate its own activity through the enhanced expression of genes involved in prostaglandin E production and signaling, which could lead to an increase in aromatase expression and E2 production, as well as the decreased expression of several nuclear receptor coactivators that could impact ER activity. Our studies highlight the diverse gene networks and metabolic and cell regulatory pathways through which this hormone operates to achieve its widespread effects on breast cancer cells.
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F. Stossi, V. S. Likhite, J. A. Katzenellenbogen, and B. S. Katzenellenbogen Estrogen-occupied Estrogen Receptor Represses Cyclin G2 Gene Expression and Recruits a Repressor Complex at the Cyclin G2 Promoter J. Biol. Chem., June 16, 2006; 281(24): 16272 - 16278. [Abstract] [Full Text] [PDF] |
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C L Wilson, A H Sims, A Howell, C J Miller, and R B Clarke Effects of oestrogen on gene expression in epithelium and stroma of normal human breast tissue. Endocr. Relat. Cancer, June 1, 2006; 13(2): 617 - 628. [Abstract] [Full Text] [PDF] |
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W. Liu, S. D. Konduri, S. Bansal, B. K. Nayak, S. A. Rajasekaran, S. M. Karuppayil, A. K. Rajasekaran, and G. M. Das Estrogen Receptor-{alpha} Binds p53 Tumor Suppressor Protein Directly and Represses Its Function J. Biol. Chem., April 14, 2006; 281(15): 9837 - 9840. [Abstract] [Full Text] [PDF] |
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W. R. Harrington, S. H. Kim, C. C. Funk, Z. Madak-Erdogan, R. Schiff, J. A. Katzenellenbogen, and B. S. Katzenellenbogen Estrogen Dendrimer Conjugates that Preferentially Activate Extranuclear, Nongenomic Versus Genomic Pathways of Estrogen Action Mol. Endocrinol., March 1, 2006; 20(3): 491 - 502. [Abstract] [Full Text] [PDF] |
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D. M. E. Harvell, J. K. Richer, D. C. Allred, C. A. Sartorius, and K. B. Horwitz Estradiol Regulates Different Genes in Human Breast Tumor Xenografts Compared with the Identical Cells in Culture Endocrinology, February 1, 2006; 147(2): 700 - 713. [Abstract] [Full Text] [PDF] |
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E. Attar and S.E. Bulun Aromatase and other steroidogenic genes in endometriosis: translational aspects Hum. Reprod. Update, January 1, 2006; 12(1): 49 - 56. [Abstract] [Full Text] [PDF] |
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T. Suzuki, Y. Miki, Y. Nakamura, T. Moriya, K. Ito, N. Ohuchi, and H. Sasano Sex steroid-producing enzymes in human breast cancer Endocr. Relat. Cancer, December 1, 2005; 12(4): 701 - 720. [Abstract] [Full Text] [PDF] |
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N. Normanno, M. Di Maio, E. De Maio, A. De Luca, A. de Matteis, A. Giordano, F. Perrone, and on behalf of the NCI-Naples Breast Cancer Group Mechanisms of endocrine resistance and novel therapeutic strategies in breast cancer Endocr. Relat. Cancer, December 1, 2005; 12(4): 721 - 747. [Abstract] [Full Text] [PDF] |
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O. Imamov, G.-J. Shim, M. Warner, and J.-A. Gustafsson Estrogen Receptor beta in Health and Disease Biol Reprod, November 1, 2005; 73(5): 866 - 871. [Abstract] [Full Text] [PDF] |
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V X Jin, H Sun, T T Pohar, S Liyanarachchi, S K Palaniswamy, T H-M Huang, and R V Davuluri ERTargetDB: an integral information resource of transcription regulation of estrogen receptor target genes J. Mol. Endocrinol., October 1, 2005; 35(2): 225 - 230. [Abstract] [Full Text] [PDF] |
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H. Kishimoto, Z. Wang, P. Bhat-Nakshatri, D. Chang, R. Clarke, and H. Nakshatri The p160 family coactivators regulate breast cancer cell proliferation and invasion through autocrine/paracrine activity of SDF-1{alpha}/CXCL12 Carcinogenesis, October 1, 2005; 26(10): 1706 - 1715. [Abstract] [Full Text] [PDF] |
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J. Frasor, J. M. Danes, C. C. Funk, and B. S. Katzenellenbogen Estrogen down-regulation of the corepressor N-CoR: Mechanism and implications for estrogen derepression of N-CoR-regulated genes PNAS, September 13, 2005; 102(37): 13153 - 13157. [Abstract] [Full Text] [PDF] |
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S. E. Bulun, Z. Lin, G. Imir, S. Amin, M. Demura, B. Yilmaz, R. Martin, H. Utsunomiya, S. Thung, B. Gurates, et al. Regulation of Aromatase Expression in Estrogen-Responsive Breast and Uterine Disease: From Bench to Treatment Pharmacol. Rev., September 1, 2005; 57(3): 359 - 383. [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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E. Peeva, J. Venkatesh, and B. Diamond Tamoxifen Blocks Estrogen-Induced B Cell Maturation but Not Survival J. Immunol., August 1, 2005; 175(3): 1415 - 1423. [Abstract] [Full Text] [PDF] |
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Y. Yamaguchi, H. Takei, K. Suemasu, Y. Kobayashi, M. Kurosumi, N. Harada, and S.-i. Hayashi Tumor-Stromal Interaction through the Estrogen-Signaling Pathway in Human Breast Cancer Cancer Res., June 1, 2005; 65(11): 4653 - 4662. [Abstract] [Full Text] [PDF] |
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J. Laganiere, G. Deblois, and V. Giguere Functional Genomics Identifies a Mechanism for Estrogen Activation of the Retinoic Acid Receptor {alpha}1 Gene in Breast Cancer Cells Mol. Endocrinol., June 1, 2005; 19(6): 1584 - 1592. [Abstract] [Full Text] [PDF] |
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D. Rai, A. Frolova, J. Frasor, A. E. Carpenter, and B. S. Katzenellenbogen Distinctive Actions of Membrane-Targeted Versus Nuclear Localized Estrogen Receptors in Breast Cancer Cells Mol. Endocrinol., June 1, 2005; 19(6): 1606 - 1617. [Abstract] [Full Text] [PDF] |
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E. R. Simpson, M. Misso, K. N. Hewitt, R. A. Hill, W. C. Boon, M. E. Jones, A. Kovacic, J. Zhou, and C. D. Clyne Estrogen--the Good, the Bad, and the Unexpected Endocr. Rev., May 1, 2005; 26(3): 322 - 330. [Full Text] [PDF] |
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J G Moggs, T C Murphy, F L Lim, D J Moore, R Stuckey, K Antrobus, I Kimber, and G Orphanides Anti-proliferative effect of estrogen in breast cancer cells that re-express ER{alpha} is mediated by aberrant regulation of cell cycle genes J. Mol. Endocrinol., April 1, 2005; 34(2): 535 - 551. [Abstract] [Full Text] [PDF] |
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T. Itoh, K. Karlsberg, I. Kijima, Y.-C. Yuan, D. Smith, J. Ye, and S. Chen Letrozole-, Anastrozole-, and Tamoxifen-Responsive Genes in MCF-7aro Cells: A Microarray Approach Mol. Cancer Res., April 1, 2005; 3(4): 203 - 218. [Abstract] [Full Text] [PDF] |
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