title: Functional proteomics identifies miRNAs to target a p27/Myc/phospho-Rb signature in breast and ovarian cancer.
abstract: The myc oncogene is overexpressed in almost half of all breast and ovarian cancers, but attempts at therapeutic interventions against myc have proven to be challenging. Myc regulates multiple biological processes, including the cell cycle, and as such is associated with cell proliferation and tumor progression. We identified a protein signature of high myc, low p27 and high phospho-Rb significantly correlated with poor patient survival in breast and ovarian cancers. Screening of a miRNA library by functional proteomics in multiple cell lines and integration of data from patient tumors revealed a panel of five microRNAs (miRNAs) (miR-124, miR-365, miR-34b*, miR-18a and miR-506) as potential tumor suppressors capable of reversing the p27/myc/phospho-Rb protein signature. Mechanistic studies revealed an RNA-activation function of miR-124 resulting in direct induction of p27 protein levels by binding to and inducing transcription on the p27 promoter region leading to a subsequent G1 arrest. Additionally, in vivo studies utilizing a xenograft model demonstrated that nanoparticle-mediated delivery of miR-124 could reduce tumor growth and sensitize cells to etoposide, suggesting a clinical application of miRNAs as therapeutics to target the functional effect of myc on tumor growth.
authors: Department of Systems Biology, UT MD Anderson Cancer Center, Houston, TX, USA.
authors: E G
authors: EG
authors: Seviour
authors: Department of Systems Biology, UT MD Anderson Cancer Center, Houston, TX, USA.
authors: V
authors: V
authors: Sehgal
authors: Department of Systems Biology, UT MD Anderson Cancer Center, Houston, TX, USA.
authors: Y
authors: Y
authors: Lu
authors: Department of Systems Biology, UT MD Anderson Cancer Center, Houston, TX, USA.
authors: Z
authors: Z
authors: Luo
authors: Department of Systems Biology, UT MD Anderson Cancer Center, Houston, TX, USA.
authors: T
authors: T
authors: Moss
authors: Department of Systems Biology, UT MD Anderson Cancer Center, Houston, TX, USA.
authors: F
authors: F
authors: Zhang
authors: MRC Biostatistics Unit, Cambridge Institute of Public Health, Cambridge, UK.
authors: S M
authors: SM
authors: Hill
authors: Department of Bioinformatics and Computational Biology, UTMDACC, Houston, TX, USA.
authors: W
authors: W
authors: Liu
authors: Department of Pediatrics, UTMDACC, Houston, TX, USA.
authors: S N
authors: SN
authors: Maiti
authors: Department of Pediatrics, UTMDACC, Houston, TX, USA.
authors: L
authors: L
authors: Cooper
authors: Department of Mathematics, University of Houston, Houston, TX, USA.
authors: R
authors: R
authors: Azencot
authors: Department of Experimental Therapeutics, UTMDACC, Houston, TX, USA.|Center for RNA Interference and Non-Coding RNA, UTMDACC, Houston, TX, USA.
authors: G
authors: G
authors: Lopez-Berestein
authors: Department of Experimental Therapeutics, UTMDACC, Houston, TX, USA.
authors: C
authors: C
authors: Rodriguez-Aguayo
authors: Department of Experimental Therapeutics, UTMDACC, Houston, TX, USA.
authors: R
authors: R
authors: Roopaimoole
authors: Division of Cancer Medicine, UTMDACC, Houston, TX, USA.
authors: C V
authors: CV
authors: Pecot
authors: Division of Cancer Medicine, UTMDACC, Houston, TX, USA.
authors: C
authors: C
authors: Pecot
authors: Department of Gynecologic Oncology, UTMDACC, Houston, TX, USA.
authors: A K
authors: AK
authors: Sood
authors: MRC Biostatistics Unit, Cambridge Institute of Public Health, Cambridge, UK.
authors: S
authors: S
authors: Mukherjee
authors: Department of Biomedical Engineering, Oregon Health Sciences University, Portland, OR, USA.
authors: J W
authors: JW
authors: Gray
authors: Department of Systems Biology, UT MD Anderson Cancer Center, Houston, TX, USA.
authors: G B
authors: GB
authors: Mills
authors: Department of Systems Biology, UT MD Anderson Cancer Center, Houston, TX, USA.
authors: P T
authors: PT
authors: Ram
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D006801:Humans; D035683:MicroRNAs / Q000502:physiology*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D010750:Phosphoproteins / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D016160:Retinoblastoma Protein / Q000235:genetics* / Q000378:metabolism; D059467:Transcriptome; D014407:Tumor Cells, Cultured
chemical_list: C509207:MIRN124 microRNA, human; D035683:MicroRNAs; D010750:Phosphoproteins; D016160:Retinoblastoma Protein; D050760:Cyclin-Dependent Kinase Inhibitor p27
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