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MicroRNA (miRNA) are short, regulatory RNA transcribed from introns (non-coding regions of a gene) or intergenic regions (stretches of DNA present between genes). Several processing steps are required to form biologically active, mature miRNA. The initial transcript, called primary miRNA (pri-mRNA), base-pairs with itself, forming a stem-loop structure. Within the nucleus, an endonuclease enzyme, called Drosha, shortens the stem-loop structure into hairpin-shaped pre-miRNA. After the pre-miRNA...
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Elucidating the Role of MicroRNA-18a in Propelling a Hybrid Epithelial-Mesenchymal Phenotype and Driving Malignant

Madhumathy G Nair1, Apoorva D Mavatkar1, Chandrakala M Naidu1

  • 1Division of Molecular Medicine, St. John's Research Institute, St. John's Medical College, Bangalore 560034, Karnataka, India.

Cells
|May 24, 2024
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Summary

Low miR-18a expression in ER-negative breast cancer drives aggressive traits like migration and stemness. This microRNA (miRNA) study reveals a subtype-specific role in tumour progression and metastasis.

Keywords:
ER-negative breast cancerchemoresistanceepithelial–mesenchymal transitionhybrid E/M phenotypemicroRNA-18astem-like cells

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Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Epigenetic changes, including microRNA (miRNA) alterations, influence tumour cell states, epithelial-mesenchymal transition (EMT), and metastasis in breast cancer.
  • The aggressive ER-negative subtype presents unique challenges in understanding tumour progression.

Purpose of the Study:

  • To investigate the role of microRNA-18a (miR-18a) in mediating a hybrid epithelial/mesenchymal (E/M) cell state in ER-negative breast cancer.
  • To evaluate the clinical relevance and functional impact of miR-18a expression in breast cancer progression.

Main Methods:

  • Analysis of miR-18a expression in patient-derived breast tumour samples (n=446) and public gene expression datasets.
  • Validation in in vitro and in vivo breast cancer models.
  • Bioinformatic analysis of miR-18a targets and associated signalling pathways, including hypoxia-inducible factor 1-alpha (HIF-1α).

Main Results:

  • Down-regulated miR-18a expression in ER-negative tumours correlates with enrichment of hybrid E/M cells.
  • These cells exhibit luminal attributes, enhanced migration, stemness, drug resistance, and immunosuppression.
  • Evidence suggests hypoxia-inducible factor 1-alpha (HIF-1α)-mediated signalling contributes to these effects.

Conclusions:

  • miR-18a plays a subtype-specific, dual role in breast cancer progression based on hormone receptor status.
  • Low miR-18a levels are associated with aggressive phenotypes in ER-negative breast cancer, potentially via HIF-1α signalling.
  • miRNA signatures, particularly miR-18a, may enable stratification of ER-negative breast cancer into clinically relevant subgroups.