Elucidating the Role of MicroRNA-18a in Propelling a Hybrid Epithelial�Mesenchymal Phenotype and Driving Malignant Progression in ER-Negative Breast Cancer

Nair, MG and Mavatkar, AD and Naidu, CM and V P, S and C E, A and Rajarajan, S and Sahoo, S and Mohan, G and Jaikumar, VS and Ramesh, RS and B S, S and Jolly, MK and Maliekal, TT and Prabhu, JS (2024) Elucidating the Role of MicroRNA-18a in Propelling a Hybrid Epithelial�Mesenchymal Phenotype and Driving Malignant Progression in ER-Negative Breast Cancer. In: Cells, 13 (10).

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Abstract

Epigenetic alterations that lead to differential expression of microRNAs (miRNAs/miR) are known to regulate tumour cell states, epithelial�mesenchymal transition (EMT) and the progression to metastasis in breast cancer. This study explores the key contribution of miRNA-18a in mediating a hybrid E/M cell state that is pivotal to the malignant transformation and tumour progression in the aggressive ER-negative subtype of breast cancer. The expression status and associated effects of miR-18a were evaluated in patient-derived breast tumour samples in combination with gene expression data from public datasets, and further validated in in vitro and in vivo breast cancer model systems. The clinical relevance of the study findings was corroborated against human breast tumour specimens (n = 446 patients). The down-regulated expression of miR-18a observed in ER-negative tumours was found to drive the enrichment of hybrid epithelial/mesenchymal (E/M) cells with luminal attributes, enhanced traits of migration, stemness, drug-resistance and immunosuppression. Further analysis of the miR-18a targets highlighted possible hypoxia-inducible factor 1-alpha (HIF-1α)-mediated signalling in these tumours. This is a foremost report that validates the dual role of miR-18a in breast cancer that is subtype-specific based on hormone receptor expression. The study also features a novel association of low miR-18a levels and subsequent enrichment of hybrid E/M cells, increased migration and stemness in a subgroup of ER-negative tumours that may be attributed to HIF-1α mediated signalling. The results highlight the possibility of stratifying the ER-negative disease into clinically relevant groups by analysing miRNA signatures. © 2024 by the authors.

Item Type:	Journal Article
Publication:	Cells
Publisher:	Multidisciplinary Digital Publishing Institute (MDPI)
Additional Information:	The copyright for this article belongs to authors.
Keywords:	beta3 integrin; breast cancer resistance protein; estrogen receptor; hormone receptor; hypoxia inducible factor 1alpha; microRNA; microRNA 18a; unclassified drug; estrogen receptor; hypoxia inducible factor 1alpha; microRNA; MIRN18A microRNA, human, Article; breast tumor; cancer growth; cell composition; cell cycle progression; cell migration; cell proliferation; cell viability; cohort analysis; colony formation; computer model; controlled study; correlation analysis; densitometry; differential expression analysis; disease free survival; down regulation; epithelial mesenchymal transition; estrogen receptor negative breast cancer; female; gene expression; gene expression profiling; gene ontology; genetic transfection; high intensity interval training; histopathology; human; human cell; immunofluorescence; immunohistochemistry; immunophenotyping; immunoreactivity; immunosuppressive treatment; in vitro study; in vivo study; MDA-MB-468 cell line; mouse; mRNA expression level; MTT assay; neoadjuvant chemotherapy; nonhuman; phenotype; prediction; protein expression; protein expression assay; quality control; real time polymerase chain reaction; regulatory T lymphocyte; RNA sequence; sequence homology; tumor associated leukocyte; tumor growth; tumor immunity; tumor invasion; tumor microenvironment; tumor xenograft; upregulation; Western blotting; Wnt signaling; wound closure assay; wound healing assay; animal; breast tumor; cell motion; disease exacerbation; gene expression regulation; genetics; metabolism; pathology; tumor cell line, Animals; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Disease Progression; Epithelial-Mesenchymal Transition; Female; Gene Expression Regulation, Neoplastic; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Mice; MicroRNAs; Phenotype; Receptors, Estrogen
Department/Centre:	Division of Interdisciplinary Sciences > Centre for Biosystems Science and Engineering
Date Deposited:	07 Aug 2024 06:18
Last Modified:	07 Aug 2024 06:18
URI:	http://eprints.iisc.ac.in/id/eprint/85254

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