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: 4.53). 02/2012; 17(1):15-21. DOI: 10.1007/s10911-012-9242-8
Source: PubMed


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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    • "Emerging evidence suggests breast CSCs reside in different states based on epithelial or mesenchymal properties (i.e. ALDH+ vs. CD44+CD24-) [8] [9]. Our gene expression profiles indicate that breast CSCs share similar profiles across the major molecular subtypes (e.g. "
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    ABSTRACT: Accumulating evidence has demonstrated that breast cancers are initiated and develop from a small population of stem-like cells termed cancer stem cells (CSCs). These cells are hypothesized to mediate tumor metastasis and contribute to therapeutic resistance. However, the molecular regulatory networks responsible for maintaining CSCs in an undifferentiated state have yet to be elucidated. In this study, we used CSC markers to isolate pure breast CSCs fractions (ALDH+ and CD44+CD24- cell populations) and the mature luminal cells (CD49f-EpCAM+) from the MCF7 cell line. Proteomic analysis was performed on these samples and a total of 3,304 proteins were identified. A label-free quantitative method was applied to analyze differentially expressed proteins. Using the criteria of greater than 2 fold changes and p value < 0.05, 305, 322 and 98 proteins were identified as significantly different in three pairwise comparisons of ALDH+ vs CD44+CD24-, ALDH+ vs CD49f-EpCAM+ and CD44+CD24- vs CD49f-EpCAM+, respectively. Pathway analysis of differentially expressed proteins by Ingenuity Pathway Analysis (IPA) revealed potential molecular regulatory networks that may regulate CSCs. Selected differential proteins were validated by Western blot assay and immunohistochemical staining. The use of proteomics analysis may increase our understanding of the underlying molecular mechanisms of breast CSCs. This may be of importance in the future development of anti-CSC therapeutics. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Proteomics 09/2015; DOI:10.1002/pmic.201500002 · 3.81 Impact Factor
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    • "Together with CD44 this protein was identified as a marker of colorectal cancer stem cells associated to the invasion and metastasis [31]. The biological network constructed using Chilibot indicates a parallel relationship between EPCAM and ITGA6 proteins and link both proteins to breast cancer [32] [33] (See Fig. 6 in [13]). On the other hand, BCAM protein is up-regulated in colon cancer and promotes malignant transformation and/or metastasis [34]. "
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    ABSTRACT: The second generation peptide CIGB-552 has a pro-apoptotic effect on H460 non-small cell lung cancer cells and displays a potent cytotoxic effect in HT-29 colon adenocarcinoma cells though its action mechanism is ill defined. Here, we present the first proteomic study of peptide effect in HT-29 cells using subcellular fractionation, protein and peptide fractionation by DF-PAGE and LC-MS/MS peptide identification. In particular, we explored the nuclear proteome of HT-29 cells at 5h treatment identifying a total of 68 differentially modulated proteins, 49 of which localize to nucleus. The differentially modulated proteins were analyzed following a system biology approach. Results pointed to a modulation of apoptosis, oxidative damage removal, NF-κB activation, inflammatory signaling and of cell adhesion and motility. Further western blot and flow-cytometry experiments confirmed both a pro-apoptotic and an anti-inflammatory effect of CIGB-552 peptide in HT-29 cells. CIGB-552 is a second generation antitumor peptide obtained from LAFL32-51 non-cyclic region that displays potent cytotoxicity in lung and colon cancer cells. Colon cancer is a common disease whose treatment so far relies on few chemotherapy drugs. Here we explored the effect of CIGB-552 peptide treatment in colon cancer using a comparative proteomics approach. This study provides knowledge of nuclear associated processes and pathways that are regulated by the peptide. We demonstrated that similar to lung cancer the peptide has a pro-apoptotic effect and an anti-inflammatory effect. Both these effects illustrate the targeting of cancer hallmarks by the peptide. We believe that these findings could be relevant in the design of future anticancer therapies using CIGB-552 peptide and give new opportunities in the treatment of colon cancer. Copyright © 2015. Published by Elsevier B.V.
    Journal of proteomics 05/2015; 126. DOI:10.1016/j.jprot.2015.05.024 · 3.89 Impact Factor
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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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