Nucleic Acids Research Advance Access originally published online on November 5, 2007
Nucleic Acids Research 2008 36(1):76-93; doi:10.1093/nar/gkm945
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Nucleic Acids Research, 2008, Vol. 36, No. 1 76-93
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Genomics |
Mechanisms of primary and secondary estrogen target gene regulation in breast cancer cells
1Institute for Research in Immunology and Cancer and Biochemistry Department, Université de Montréal, C.P. 6128 Succursale Centre Ville, Montréal, QC H3C 3J7 and 2Department of Physiology and Department of Medicine, McGill University, Montréal, QC H3A 1A4, Canada
*To whom correspondence should be addressed. Tel: +514 343 7166; Fax: +514 343 6843; Email: sylvie.mader{at}umontreal.ca
Received May 11, 2007. Revised October 15, 2007. Accepted October 15, 2007.
Estrogen receptors (ERs), which mediate the proliferative action of estrogens in breast cancer cells, are ligand-dependent transcription factors that regulate expression of their primary target genes through several mechanisms. In addition to direct binding to cognate DNA sequences, ERs can be recruited to DNA through other transcription factors (tethering), or affect gene transcription through modulation of signaling cascades by non-genomic mechanisms of action. To better characterize the mechanisms of gene regulation by estrogens, we have identified more than 700 putative primary and about 1300 putative secondary target genes of estradiol in MCF-7 cells through microarray analysis performed in the presence or absence of the translation inhibitor cycloheximide. Although siRNA-mediated inhibition of ER
expression antagonized the effects of estradiol on up- and down-regulated primary target genes, estrogen response elements (EREs) were enriched only in the vicinity of up-regulated genes. Binding sites for several other transcription factors, including proteins known to tether ER, were enriched in up- and/or down-regulated primary targets. Secondary estrogen targets were particularly enriched in sites for E2F family members, several of which were transcriptionally regulated by estradiol, consistent with a major role of these factors in mediating the effects of estrogens on gene expression and cellular growth.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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