Epithelial-mesenchymal transition transcription factors and miRNAs: “Plastic surgeons” of breast cancer

Abstract

Growing evidence suggests that breast cancer cell plasticity arises due to a partial reactivation of epithelial-mesenchymal transition (EMT) programs in order to give cells pluripotency, leading to a stemness-like phenotype. A complete EMT would be a dead end program that would render cells unable to fully metastasize to distant organs. Evoking the EMT-mesenchymal-to-epithelial transition (MET) cascade promotes successful colonization of distal target tissues. It is unlikely that direct reprogramming or trans-differentiation without passing through a pluripotent stage would be the preferred mechanism during tumor progression. This review focuses on key EMT transcriptional regulators, EMT-transcription factors involved in EMT (TFs) and the miRNA pathway, which are deregulated in breast cancer, and discusses their implications in cancer cell plasticity. Cross-regulation between EMT-TFs and miRNAs, where miRNAs act as co-repressors or co-activators, appears to be a pivotal mechanism for breast cancer cells to acquire a stem cell-like state, which is implicated both in breast metastases and tumor recurrence. As a master regulator of miRNA biogenesis, the ribonuclease type III endonuclease Dicer plays a central role in EMT-TFs/miRNAs regulating networks. All these EMT-MET key regulators represent valuable new prognostic and predictive markers for breast cancer as well as promising new targets for drug-resistant breast cancers.

Keywords: Embryonic transcription factors, Epithelial to mesenchymal transition, Breast cancer, MicroRNAs, Dicer, Feedback loop

Core tip: Epithelial-mesenchymal transition (EMT) and the reverse mesenchymal-epithelial transition (MET) are both involved in breast cancer plasticity. Embryonic transcription factors and miRNAs are key players regulating the balance between these two processes allowing cells that underwent EMT to transiently re-acquire epithelial phenotype. Here we highlighted the complex transcription factors/miRNAs regulation networks involved in EMT-MET during breast cancer progression and the central role played by Dicer, the key enzyme of miRNAs processing, in EMT process. These key regulators of EMT-MET may represent predictive markers and potential therapeutic targets for breast cancers.