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Nucleic Acids Res. 2019 Jan 18. doi: 10.1093/nar/gkz016. [Epub ahead of print]

Identification of microRNA clusters cooperatively acting on epithelial to mesenchymal transition in triple negative breast cancer.

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Institut Curie, 26 rue d'Ulm, F-75005 Paris, France.
PSL Research University, F-75005 Paris, France.
Inserm, U900, F-75005, Paris France.
Mines Paris Tech, F-77305 cedex Fontainebleau, France.
Computational Systems Biology Team, Institut de Biologie de l'Ecole Normale Supérieure, CNRS UMR8197, INSERM U1024, Ecole Normale Supérieure, Paris Sciences et Lettres Research University, 75005 Paris, France.
Institute of Molecular Bioimaging and Physiology, National Research Council (IBFM-CNR), Italy.
Institut Curie, PSL Research University, Department of Translational Research, Breast Cancer Biology Group, Paris, France.
Department of Physics and INFN, Università degli Studi di Torino, Turin, Italy.


MicroRNAs play important roles in many biological processes. Their aberrant expression can have oncogenic or tumor suppressor function directly participating to carcinogenesis, malignant transformation, invasiveness and metastasis. Indeed, miRNA profiles can distinguish not only between normal and cancerous tissue but they can also successfully classify different subtypes of a particular cancer. Here, we focus on a particular class of transcripts encoding polycistronic miRNA genes that yields multiple miRNA components. We describe 'clustered MiRNA Master Regulator Analysis (ClustMMRA)', a fully redesigned release of the MMRA computational pipeline (MiRNA Master Regulator Analysis), developed to search for clustered miRNAs potentially driving cancer molecular subtyping. Genomically clustered miRNAs are frequently co-expressed to target different components of pro-tumorigenic signaling pathways. By applying ClustMMRA to breast cancer patient data, we identified key miRNA clusters driving the phenotype of different tumor subgroups. The pipeline was applied to two independent breast cancer datasets, providing statistically concordant results between the two analyses. We validated in cell lines the miR-199/miR-214 as a novel cluster of miRNAs promoting the triple negative breast cancer (TNBC) phenotype through its control of proliferation and EMT.


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