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 around 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 evidences 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 evidences 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 molecular level to contribute to cancer drug resistance. Our results 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 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 pathway in CSCs.

Towards Unravelling the Role of ERα-Targeting miRNAs in the Exosome-Mediated Transferring of the Hormone Resistance

“…Intriguing new data suggest that miRNAs will be used to overcome resistance. Bernice Monchusi and Mandeep Kaur suggested that targeting the miRNAs hsa-miR-34a-5p and hsa-miR-373-3p could provide a way to alter the cell's response to drugs via modulating cholesterol pathways in cancer stem cells [99].…”

Impact of De Novo Cholesterol Biosynthesis on the Initiation and Progression of Breast Cancer

“…They are small (~18-25 nucleotides) nonencoding RNAs that can modulate the expression of the genes involved in the pathway [87]. A recent study using bioinformatics analysis [88] has revealed that hsa-miR-34a-5p and hsa-miR-373-3p can affect the expression of several genes related to CHOL, including INSIG2. This gene codes for insulin-induced gene 2, an endoplasmic reticulum protein that acts as a negative regulator of CHOL biosynthesis by retaining the SCAP-SREBP complex in the endoplasmic reticulum.…”