Abstract
The complexity of the ER-negative subtype of breast cancer arises due to the heterogeneous nature of the disease rendering them more aggressive and this poses a challenge to effective treatment and eventually the prognosis of the patients. We have explored the miRNA regulation of altered molecular signatures and the effect on tumour progression in ER-negative breast cancer. Using breast tumour specimens, gene expression data from public datasets and in-vitro and in-vivo model systems we have shown that low-levels of miR-18a in ER-negative tumours drives enrichment of hybrid Epithelial/Mesenchymal (E/M) cells with luminal attributes. On inhibition of miR-18a in ER-negative breast cancer cell lines, the cells showed traits of increased migration, stemness and drug-resistance. miR-18a/low tumours were also associated with increased expression of genes associated with EMT, stemness, drug resistance and immune-suppression. Further analysis of the miR-18a targets pointed out at a possible HIF-1α mediated signalling in these tumours. HIF-1α inhibition reduced the enrichment of the hybrid E/M cells and decreased the migratory ability of miR-18a/low cells. Our study reports for the first time a dual role of miR-18a in breast cancer that is subtype specific based on hormone receptor expression and a novel association of low miR-18a levels and enrichment of hybrid E/M cells. The results highlight the possibility of stratifying the ER-negative disease into clinically relevant groups by analysing epigenetic signatures.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Conflicting interests The authors have no conflict of interest.
Ethics approvals and consent to participate: All procedures performed in the studies involving human participants were in accordance with the ethical standards of both St. John’s Medical College and Hospital (No. 62/2008) and Rangadore Memorial Hospital (RMHEC/02/2010) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. A written informed consent for utilization of clinical data was obtained from all enrolled patients. In-vitro experiments were performed at SJRI in accordance with Institutional Biosafety Committee regulations (IBSC/SJRI/01-04/1905/ 2022). Xenograft experiments were performed at the Animal Research Facility, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram in accordance with ethical standards (AEC No: IAEC/876/TM/2022).