Identification of microRNA clusters cooperatively acting on Epithelial to Mesenchymal Transition in Triple Negative Breast Cancer

TL;DR

This study introduces ClustMMRA, a computational pipeline to identify microRNA clusters that drive cancer subtypes, validated by discovering a novel miRNA cluster promoting triple negative breast cancer through proliferation and EMT regulation.

Contribution

The paper presents ClustMMRA, an improved computational method for identifying clustered miRNAs involved in cancer subtyping, validated on breast cancer datasets.

Findings

Identified miR-199/miR-214 as a novel cluster promoting triple negative breast cancer.

Validated the miRNA cluster's role in proliferation and EMT in cell lines.

Demonstrated concordant results across independent datasets.

Abstract

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 signalling 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 analysis. We validated in cell lines the miR-199/miR-214 as a novel cluster of miRNAs promoting the triple negative subtype phenotype through its control of proliferation and EMT.