Elucidating the Role of MicroRNA-18a in Propelling a Hybrid Epithelial–Mesenchymal Phenotype and Driving Malignant Progression in ER-Negative Breast Cancer
Madhumathy G. Nair,
Apoorva D. Mavatkar,
Chandrakala M. Naidu,
Snijesh V. P.,
Anupama C. E.,
Savitha Rajarajan,
Sarthak Sahoo,
Gayathri Mohan,
Vishnu Sunil Jaikumar,
Rakesh S. Ramesh,
Srinath B. S.,
Mohit Kumar Jolly,
Tessy Thomas Maliekal,
Jyothi S. Prabhu
Affiliations
Madhumathy G. Nair
Division of Molecular Medicine, St. John’s Research Institute, St. John’s Medical College, Bangalore 560034, Karnataka, India
Apoorva D. Mavatkar
Division of Molecular Medicine, St. John’s Research Institute, St. John’s Medical College, Bangalore 560034, Karnataka, India
Chandrakala M. Naidu
Division of Molecular Medicine, St. John’s Research Institute, St. John’s Medical College, Bangalore 560034, Karnataka, India
Snijesh V. P.
Division of Molecular Medicine, St. John’s Research Institute, St. John’s Medical College, Bangalore 560034, Karnataka, India
Anupama C. E.
Division of Molecular Medicine, St. John’s Research Institute, St. John’s Medical College, Bangalore 560034, Karnataka, India
Savitha Rajarajan
Division of Molecular Medicine, St. John’s Research Institute, St. John’s Medical College, Bangalore 560034, Karnataka, India
Sarthak Sahoo
Department of Bioengineering, Indian Institute of Science (Bangalore), Bengaluru 560012, Karnataka, India
Gayathri Mohan
Cancer Research, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram 695014, Kerala, India
Vishnu Sunil Jaikumar
Animal Research Facility, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram 695014, Kerala, India
Rakesh S. Ramesh
Department of Surgical Oncology, St. John’s Medical College and Hospital, Bangalore 560034, Karnataka, India
Srinath B. S.
Department of Surgical Oncology, Sri Shankara Cancer Hospital and Research Centre, Bangalore 560004, Karnataka, India
Mohit Kumar Jolly
Department of Bioengineering, Indian Institute of Science (Bangalore), Bengaluru 560012, Karnataka, India
Tessy Thomas Maliekal
Cancer Research, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram 695014, Kerala, India
Jyothi S. Prabhu
Division of Molecular Medicine, St. John’s Research Institute, St. John’s Medical College, Bangalore 560034, Karnataka, India
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.
