Liu, S., Patel, S. H., Ginestier, C., Ibarra, I., Martin-Trevino, R., Bai, S., McDermott, S. P., Shang, L., Ke, J., Ou, S. J., Heath, A., Zhang, K. J., Korkaya, H., Clouthier, S. G., Charafe-Jauffret, E., Birnbaum, D., Hannon, G. J., Wicha, M. S. (2012) MicroRNA93 regulates proliferation and differentiation of normal and malignant breast stem cells. PLoS Genetics, 8 (6). ISSN 15537390 (ISSN)
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Abstract
MicroRNAs (miRNAs) play important roles in normal cellular differentiation and oncogenesis. microRNA93 (mir-93), a member of the mir106b-25 cluster, located in intron 13 of the MCM7 gene, although frequently overexpressed in human malignancies may also function as a tumor suppressor gene. Using a series of breast cancer cell lines representing different stages of differentiation and mouse xenograft models, we demonstrate that mir-93 modulates the fate of breast cancer stem cells (BCSCs) by regulating their proliferation and differentiation states. In "claudin low" SUM159 cells, expression of mir-93 induces Mesenchymal-Epithelial Transition (MET) associated with downregulation of TGFβ signaling and downregulates multiple stem cell regulatory genes, including JAK1, STAT3, AKT3, SOX4, EZH1, and HMGA2, resulting in cancer stem cell (CSC) depletion. Enforced expression of mir-93 completely blocks tumor development in mammary fat pads and development of metastases following intracardiac injection in mouse xenografts. The effect of mir-93 on the CSC population is dependent on the cellular differentiation state, with mir-93 expression increasing the CSC population in MCF7 cells that display a more differentiated "luminal" phenotype. mir-93 also regulates the proliferation and differentiation of normal breast stem cells isolated from reduction mammoplasties. These studies demonstrate that miRNAs can regulate the states and fates of normal and malignant mammary stem cells, findings which have important biological and clinical implications. © 2012 Liu et al.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | claudin microRNA microRNA 93 transforming growth factor beta unclassified drug cell cycle protein DNA binding protein MCM7 protein, human nuclear protein AKT3 gene animal experiment animal model article breast cancer breast carcinogenesis cancer staging cancer stem cell cell differentiation cell fate cell population cell proliferation controlled study down regulation epithelial mesenchymal transition EZH1 gene female gene expression regulation gene function HMGA2 gene human human cell JAK1 gene MCM7 gene mouse nonhuman regulator gene regulatory mechanism Sox4 gene STAT3 gene tumor gene tumor suppressor gene tumor xenograft animal breast tumor cell transformation cytology experimental neoplasm genetics mammary gland metabolism tumor cell line Animals Breast Neoplasms Cell Cycle Proteins Cell Line, Tumor Cell Transformation, Neoplastic DNA-Binding Proteins Epithelial-Mesenchymal Transition Gene Expression Regulation, Neoplastic Humans Mammary Glands, Human Mice MicroRNAs Neoplasms, Experimental Neoplastic Stem Cells Nuclear Proteins |
| Subjects: | diseases & disorders > cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification bioinformatics > genomics and proteomics > genetics & nucleic acid processing diseases & disorders > cancer > cancer types > breast cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > miRNA bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > miRNA therapies > stem cells |
| CSHL Authors: | |
| Communities: | CSHL Cancer Center Shared Resources > Bioinformatics Service CSHL Cancer Center Shared Resources > DNA Sequencing Service CSHL labs > Hannon lab CSHL Cancer Center Program > Cancer Genetics |
| Depositing User: | Matt Covey |
| Date: | 2012 |
| Date Deposited: | 09 Jan 2013 16:11 |
| Last Modified: | 14 Oct 2015 19:16 |
| PMCID: | PMC3369932 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/26415 |
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