title: Global microRNA level regulation of EGFR-driven cell-cycle protein network in breast cancer.
abstract: The EGFR-driven cell-cycle pathway has been extensively studied due to its pivotal role in breast cancer proliferation and pathogenesis. Although several studies reported regulation of individual pathway components by microRNAs (miRNAs), little is known about how miRNAs coordinate the EGFR protein network on a global miRNA (miRNome) level. Here, we combined a large-scale miRNA screening approach with a high-throughput proteomic readout and network-based data analysis to identify which miRNAs are involved, and to uncover potential regulatory patterns. Our results indicated that the regulation of proteins by miRNAs is dominated by the nucleotide matching mechanism between seed sequences of the miRNAs and 3'-UTR of target genes. Furthermore, the novel network-analysis methodology we developed implied the existence of consistent intrinsic regulatory patterns where miRNAs simultaneously co-regulate several proteins acting in the same functional module. Finally, our approach led us to identify and validate three miRNAs (miR-124, miR-147 and miR-193a-3p) as novel tumor suppressors that co-target EGFR-driven cell-cycle network proteins and inhibit cell-cycle progression and proliferation in breast cancer.
authors.affiliation: Division of Molecular Genome Analysis, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Uhlmann
authors.forename: Heiko
authors.initials: H
authors.lastname: Mannsperger
authors.forename: Jitao David
authors.initials: JD
authors.lastname: Zhang
authors.forename: Emöke-Ágnes
authors.initials: EÁ
authors.lastname: Horvat
authors.forename: Christian
authors.initials: C
authors.lastname: Schmidt
authors.forename: Moritz
authors.initials: M
authors.lastname: Küblbeck
authors.forename: Frauke
authors.initials: F
authors.lastname: Henjes
authors.forename: Aoife
authors.initials: A
authors.lastname: Ward
authors.forename: Ulrich
authors.initials: U
authors.lastname: Tschulena
authors.forename: Katharina
authors.initials: K
authors.lastname: Zweig
authors.forename: Ulrike
authors.initials: U
authors.lastname: Korf
authors.forename: Stefan
authors.initials: S
authors.lastname: Wiemann
authors.forename: Ozgür
authors.initials: O
authors.lastname: Sahin
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks / Q000502:physiology; D018773:Genes, erbB-1 / Q000502:physiology*; D057166:High-Throughput Screening Assays; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics* / Q000502:physiology; D008954:Models, Biological; D011485:Protein Binding / Q000235:genetics; D040901:Proteomics / Q000379:methods; D059467:Transcriptome / Q000235:genetics / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D018797:Cell Cycle Proteins; C509207:MIRN124 microRNA, human; C572377:MIRN147 microRNA, human; C546818:MIRN193 microRNA, human; D035683:MicroRNAs