Nucleic Acids Research Advance Access originally published online on June 14, 2009
Nucleic Acids Research 2009 37(14):4850-4861; doi:10.1093/nar/gkp500
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Nucleic Acids Research, 2009, Vol. 37, No. 14 4850-4861
© 2009 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.
Gene Regulation, Chromatin and Epigenetics |
Estradiol-regulated microRNAs control estradiol response in breast cancer cells
1Department of Surgery, 2Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 3Department of Cell and Developmental Biology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, 4Department of Medical Oncology, Dana-Farber Medical School, Harvard Medical School, Boston, MA and 5Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA
*To whom correspondence should be addressed. Tel: +1 317 278 2238; Fax: +1 317 274 0396; Email: hnakshat{at}iupui.edu
Received May 4, 2009. Revised May 22, 2009. Accepted May 24, 2009.
Estradiol (E2) regulates gene expression at the transcriptional level by functioning as a ligand for estrogen receptor alpha (ER
) and estrogen receptor beta (ERβ). E2-inducible proteins c-Myc and E2Fs are required for optimal ER activity and secondary estrogen responses, respectively. We show that E2 induces 21 microRNAs and represses seven microRNAs in MCF-7 breast cancer cells; these microRNAs have the potential to control 420 E2-regulated and 757 non-E2-regulated mRNAs at the post-transcriptional level. The serine/threonine kinase, AKT, alters E2-regulated expression of microRNAs. E2 induced the expression of eight Let-7 family members, miR-98 and miR-21 microRNAs; these microRNAs reduced the levels of c-Myc and E2F2 proteins. Dicer, a ribonuclease III enzyme required for microRNA processing, is also an E2-inducible gene. Several E2-regulated microRNA genes are associated with ER-binding sites or located in the intragenic region of estrogen-regulated genes. We propose that the clinical course of ER-positive breast cancers is dependent on the balance between E2-regulated tumor-suppressor microRNAs and oncogenic microRNAs. Additionally, our studies reveal a negative-regulatory loop controlling E2 response through microRNAs as well as differences in E2-induced transcriptome and proteome.