Estradiol-regulated microRNAs control estradiol response in breast cancer cells.

Abstract

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

• Authors: 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
• Journal: Nucleic acids research (Nucleic Acids Res) Vol. 37 Issue 14 Pg. 4850-61 (Aug 2009) ISSN: 1362-4962 [Electronic] England
• PMID: 19528081 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• E2F Transcription Factors
• Estrogen Receptor alpha
• MIRN198 microRNA, human
• MIRN21 microRNA, human
• MYC protein, human
• MicroRNAs
• Proto-Oncogene Proteins c-myc
• Estradiol
• Proto-Oncogene Proteins c-akt
• Ribonuclease III

Topics

• Binding Sites
• Breast Neoplasms (genetics, metabolism)
• Cell Line, Tumor
• E2F Transcription Factors (biosynthesis, genetics)
• Estradiol (pharmacology)
• Estrogen Receptor alpha (metabolism)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• MicroRNAs (genetics, metabolism)
• Proto-Oncogene Proteins c-akt (genetics)
• Proto-Oncogene Proteins c-myc (biosynthesis, genetics)
• Regulatory Elements, Transcriptional
• Ribonuclease III (biosynthesis, genetics)