Estradiol-regulated microRNAs control estradiol response in breast cancer cells

Poornima Bhat-Nakshatri, Guohua Wang, Nikail R. Collins, Michael J. Thomson, Tim R. Geistlinger, Jason S. Carroll, Myles Brown, Scott Hammond, Edward F. Srour, Yunlong Liu, Harikrishna Nakshatri

Research output: Contribution to journalArticle

239 Scopus citations

Abstract

Estradiol (E2) regulates gene expression at the transcriptional level by functioning as a ligand for estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). E2-inducible proteins c-Myc and E2Fs are required for optimal ERα 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 ERα-binding sites or located in the intragenic region of estrogen-regulated genes. We propose that the clinical course of ERα-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.

Original languageEnglish (US)
Pages (from-to)4850-4861
Number of pages12
JournalNucleic acids research
Volume37
Issue number14
DOIs
StatePublished - 2009

ASJC Scopus subject areas

  • Genetics

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    Bhat-Nakshatri, P., Wang, G., Collins, N. R., Thomson, M. J., Geistlinger, T. R., Carroll, J. S., Brown, M., Hammond, S., Srour, E. F., Liu, Y., & Nakshatri, H. (2009). Estradiol-regulated microRNAs control estradiol response in breast cancer cells. Nucleic acids research, 37(14), 4850-4861. https://doi.org/10.1093/nar/gkp500