Estradiol-regulated microRNAs control estradiol response in breast cancer cells.
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.
Bhat-Nakshatri
Poornima
P
Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.
Wang
Guohua
G
Collins
Nikail R
NR
Thomson
Michael J
MJ
Geistlinger
Tim R
TR
Carroll
Jason S
JS
Brown
Myles
M
Hammond
Scott
S
Srour
Edward F
EF
Liu
Yunlong
Y
Nakshatri
Harikrishna
H
D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D050684:E2F Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics; D050436:Regulatory Elements, Transcriptional; D043244:Ribonuclease III / Q000096:biosynthesis / Q000235:genetics
D050684:E2F Transcription Factors; D047628:Estrogen Receptor alpha; C535221:MIRN198 microRNA, human; C524940:MIRN21 microRNA, human; C489427:MYC protein, human; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D004958:Estradiol; D051057:Proto-Oncogene Proteins c-akt; D043244:Ribonuclease III