MiRNAs as Modulators of Cholesterol in Breast Cancer Stem Cells: An Approach to Overcome Drug Resistance in Cancer.

Abstract

It has been postulated that a small number of Cancer Stem Cells (CSCs) buried in tumour mass drive cancer growth and impart cancer drug resistance. However, their eradication has not been achieved so far as the mechanistic understanding of CSCs' role in cancer development and growth is limited. The cholesterol accumulation and efflux processes have been shown to play an important role in maintaining cell's integrity and its sensitivity towards drugs, as altered cholesterol pathways contribute to cancer drug resistance. Emerging pieces of evidence have indicated miRNAs as regulators of CSCs, and also as regulators of cholesterol pathways in cancer cells, but a link between the two has not been fully established so far. In this review, we have collated key signalling pathways and published evidence emphasising the involvement of miRNAs and cholesterol in CSCs related drug resistance. Additionally, we have used bioinformatics analysis to identify miRNAs that may modulate cholesterol pathways in CSCs at a molecular level to contribute to cancer drug resistance. Our results show that two miRNAs (hsa-miR-34a-5p and hsa-miR-373-3p) interact and bind to two known Breast CSC markers (CD44 and CD24) and mediate the expression of several cholesterol-related genes (INSIG2, APOL2, CYP51A1, HDLB, and DHCR7). Furthermore, survival analysis of the breast cancer patients' gene expression data revealed that higher expression of these genes is associated with poor disease-free survival. We, therefore, propose that targeting these two miRNAs could possibly provide a way to alter cell's response to drugs via modulating cholesterol pathways in CSCs.