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MicroRNA93 regulates proliferation and differentiation of normal and malignant breast stem cells.

Liu S, Patel SH, Ginestier C, Ibarra I, Martin-Trevino R, Bai S, McDermott SP, Shang L, Ke J, Ou SJ, Heath A, Zhang KJ, Korkaya H, Clouthier SG, Charafe-Jauffret E, Birnbaum D, Hannon GJ, Wicha MS - PLoS Genet. (2012)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Comprehensive Cancer Center, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA. sulingl@med.umich.edu

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.

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A hypothetic model illustrating regulation of normal and malignant mammary stem cell states and fates by mir-93.
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pgen-1002751-g008: A hypothetic model illustrating regulation of normal and malignant mammary stem cell states and fates by mir-93.

Mentions: In summary, our experiments suggest that CSCs can exist in two alternative epithelial and mesenchymal states, the balance of which is regulated by miRNAs including mir-93 (Figure 8). The mesenchymal state associated with an invasive phenotype characterized by quiescence and low mir-93 expression is maintained by growth factors such as TGFβ. Upon activation of cellular proliferation, MYC and E2F are induced leading to expression of MCM7, a licensing factor required for DNA synthesis. Concomitantly, mir-93 and its related miRNA cluster is co-synthesized which promotes further proliferation while simultaneously downregulating TGFβ signaling. This facilitates a mesenchymal to epithelial transition in the CSC population characterized by decreased invasiveness and increased proliferation. Continued expression of mir-93 simultaneously downregulates a number of stem cell self-renewal pathways including JAK/STAT, AKT, EZH1 and HMGH2, promoting cellular differentiation and depleting the CSC population. The model depicted in Figure 8 is consistent with our observation that mir-93 level is highest in the EpCAM+CD49f+ normal mammary cells and decreased with terminal differentiation. In contrast, the effects of mir-93 depend on the cellular differentiation state accounting for differences we observed in claudinlow, basal and luminal breast cancers, with mir-93 level highest in the luminal MCF7 cell line compared to basal HCC1954 and claudinlow SUM159 cell lines. MCF7 cells are highly proliferative although unlike normal mammary cells incapable of terminal differentiation (Figure 8). The existence of alternative CSC states, associated with expression of different protein markers has important implications for understanding the plasticity of CSCs. For example, it has been claimed that CSCs may be generated from non-CSC tumor populations through induction of EMT [31]. However, the existence of alternative CSC state suggests that the acquisition of stem cell markers may reflect transition of CSC states rather than generation of CSCs from non-CSC populations. In addition, the existence of multiple stem cell states suggests the necessity of developing of therapeutic strategies capable of effectively targeting CSCs in all of these states.


MicroRNA93 regulates proliferation and differentiation of normal and malignant breast stem cells.

Liu S, Patel SH, Ginestier C, Ibarra I, Martin-Trevino R, Bai S, McDermott SP, Shang L, Ke J, Ou SJ, Heath A, Zhang KJ, Korkaya H, Clouthier SG, Charafe-Jauffret E, Birnbaum D, Hannon GJ, Wicha MS - PLoS Genet. (2012)

A hypothetic model illustrating regulation of normal and malignant mammary stem cell states and fates by mir-93.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3369932&req=5

pgen-1002751-g008: A hypothetic model illustrating regulation of normal and malignant mammary stem cell states and fates by mir-93.
Mentions: In summary, our experiments suggest that CSCs can exist in two alternative epithelial and mesenchymal states, the balance of which is regulated by miRNAs including mir-93 (Figure 8). The mesenchymal state associated with an invasive phenotype characterized by quiescence and low mir-93 expression is maintained by growth factors such as TGFβ. Upon activation of cellular proliferation, MYC and E2F are induced leading to expression of MCM7, a licensing factor required for DNA synthesis. Concomitantly, mir-93 and its related miRNA cluster is co-synthesized which promotes further proliferation while simultaneously downregulating TGFβ signaling. This facilitates a mesenchymal to epithelial transition in the CSC population characterized by decreased invasiveness and increased proliferation. Continued expression of mir-93 simultaneously downregulates a number of stem cell self-renewal pathways including JAK/STAT, AKT, EZH1 and HMGH2, promoting cellular differentiation and depleting the CSC population. The model depicted in Figure 8 is consistent with our observation that mir-93 level is highest in the EpCAM+CD49f+ normal mammary cells and decreased with terminal differentiation. In contrast, the effects of mir-93 depend on the cellular differentiation state accounting for differences we observed in claudinlow, basal and luminal breast cancers, with mir-93 level highest in the luminal MCF7 cell line compared to basal HCC1954 and claudinlow SUM159 cell lines. MCF7 cells are highly proliferative although unlike normal mammary cells incapable of terminal differentiation (Figure 8). The existence of alternative CSC states, associated with expression of different protein markers has important implications for understanding the plasticity of CSCs. For example, it has been claimed that CSCs may be generated from non-CSC tumor populations through induction of EMT [31]. However, the existence of alternative CSC state suggests that the acquisition of stem cell markers may reflect transition of CSC states rather than generation of CSCs from non-CSC populations. In addition, the existence of multiple stem cell states suggests the necessity of developing of therapeutic strategies capable of effectively targeting CSCs in all of these states.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Comprehensive Cancer Center, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA. sulingl@med.umich.edu

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.

Show MeSH
Related in: MedlinePlus