Global microRNA level regulation of EGFR-driven cell-cycle protein network in breast cancer

Stefan Uhlmann, Heiko Mannsperger, Jitao David Zhang, Emöke Ágnes Horvat, Christian Schmidt, Moritz Küblbeck, Frauke Henjes, Aoife Ward, Ulrich Tschulena, Katharina Zweig, Ulrike Korf, Stefan Wiemann, Özgür Sahin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

127 Scopus citations

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′2-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.

Original languageEnglish (US)
Article number570
JournalMolecular Systems Biology
Volume8
DOIs
StatePublished - 2012

Keywords

  • EGFR signaling
  • breast cancer
  • miRNA-protein interaction network
  • microRNA
  • network analysis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)
  • Applied Mathematics

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