Role of microRNAs in the regulation of breast cancer stem cells

Comprehensive Cancer Center, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109-5942, USA.
Journal of Mammary Gland Biology and Neoplasia (Impact Factor: 5). 02/2012; 17(1):15-21. DOI: 10.1007/s10911-012-9242-8
Source: PubMed

ABSTRACT There is increasing evidence that many human cancers, including breast cancer, are driven and maintained by cancer stem cells (CSCs) which mediate tumor metastasis and contribute to treatment resistance and relapse. Our group was the first to describe "breast cancer stem cells" (BCSCs) characterized by expression of the cell surface markers ESA and CD44 and the absence of expression of the marker CD24. More recently, we have demonstrated that breast cancer cells contain subpopulations with stem cell properties that can be isolated by virtue of their expression of Aldehyde dehydrogenase (ALDH) as assessed by the Aldefluor assay. Interestingly, these markers identify overlapping, but not identical cell populations. Recent studies have suggested similarities between cancer stem cells and the epithelial mesenchymal transition (EMT) state. Our studies suggest that both normal and malignant breast stem cells exist in distinct, inter-convertible states (EMT and MET), the inter-conversion of which is regulated by microRNAs. EMT-like CSCs have a mesenchymal morphology, are largely quiescent, invasive and characterized by expression of the CSC markers CD24(-)CD44(+) and are EpCAM(-)CD49f(+). In contrast, the MET (mesenchymal epithelial transition) state of CSCs is characterized by active self-renewal and expression of the CSC markers ALDH and EpCAM(+)CD49f(+). A subpopulation of cells expressing both CD24(-)CD44(+) and ALDH may represent cells in transition between these states. This transition is regulated by signals originating in the microenvironment which in turn modulate microRNA networks in the CSC populations. The existence of multiple stem cell states suggests the necessity of developing therapeutic strategies capable of effectively targeting CSCs in all of these states. In addition, since CSC states are regulated by miRNAs, these small non-coding RNAs may be useful therapeutic agents to target CSCs.

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Available from: Shawn G Clouthier, Jul 28, 2015
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    • "The symbiosis between a CAF and an epithelial cancer cell leads to various epigenetic events, coordinated by cell-cell signaling through various cytokines or even vesicle-like structures known as exosomes [29] [64]. The cancer cell may acquire a stem-like characteristic after having lost apical-basal polarity, reproducing the exact epithelial-to-mesenchymal transition found in embryogenesis and wound healing [19] [53] [76]. Several cytokines, initially described in embryology and recently in oncology, such as the chemokine CXCL12 or SDF-1α, and its co-receptor, CXCR4, appear to play a salient role in breast cancer metastasis to the brain, lung and vertebral bodies [71] [89]. "
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    • "Accumulating evidence indicates that miRNAs play important roles in regulating tumor progression [30] [31]. Although till now, there are few reports about miRNA expression profiles for NSCLC CSCs/CSLCs, many researches have published miRNA expression profiles in breast and prostate CSCs/CSLCs [32] [33]. According to experimental results from Liu et al. [33], although CSCs/CSLCs from different cell types exhibited overall distinct miRNA expression profiles, all CSCs/CSLCs commonly express certain miRNAs. "
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    • "Using a squamous cell carcinoma model, it was reported that miR-138 regulated EMT by targeting multiple components of the EMT pathways, such as ZEB2 and the epigenetic regulator EZH2. Both are repressors of E-cadherin expression (Liu et al. 2012a,b). miR-191 was downregulated in FAs, FTC, and follicular variant of PTCs by targeting CDK6, a serine–threonine kinase involved in the control of cell cycle progression (Colamaio et al. 2011). "
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