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MicroRNA-205 signaling regulates mammary stem cell fate and tumorigenesis
Chi-Hong Chao, … , Jer-Yen Yang, Chun-Ju Chang
Chi-Hong Chao, … , Jer-Yen Yang, Chun-Ju Chang
Published June 9, 2014
Citation Information: J Clin Invest. 2014;124(7):3093-3106. https://doi.org/10.1172/JCI73351.
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Research Article Oncology

MicroRNA-205 signaling regulates mammary stem cell fate and tumorigenesis

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Abstract

Dysregulation of epigenetic controls is associated with tumorigenesis in response to microenvironmental stimuli; however, the regulatory pathways involved in epigenetic dysfunction are largely unclear. We have determined that a critical epigenetic regulator, microRNA-205 (miR-205), is repressed by the ligand jagged1, which is secreted from the tumor stroma to promote a cancer-associated stem cell phenotype. Knockdown of miR-205 in mammary epithelial cells promoted epithelial-mesenchymal transition (EMT), disrupted epithelial cell polarity, and enhanced symmetric division to expand the stem cell population. Furthermore, miR-205–deficient mice spontaneously developed mammary lesions, while activation of miR-205 markedly diminished breast cancer stemness. These data provide evidence that links tumor microenvironment and microRNA-dependent regulation to disruption of epithelial polarity and aberrant mammary stem cell division, which in turn leads to an expansion of stem cell population and tumorigenesis. This study elucidates an important role for miR-205 in the regulation of mammary stem cell fate, suggesting a potential therapeutic target for limiting breast cancer genesis.

Authors

Chi-Hong Chao, Chao-Ching Chang, Meng-Ju Wu, How-Wen Ko, Da Wang, Mien-Chie Hung, Jer-Yen Yang, Chun-Ju Chang

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Figure 1

The ligand jagged1 significantly represses miR-205 to promote EMT and stem cell phenotype.

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The ligand jagged1 significantly represses miR-205 to promote EMT and st...
(A) Expression levels of the most significantly altered miRNAs in HMECs treated with 40 μM jagged1 or the control peptide for 1 day using genome-wide miRNA-PCR array (n = 3, *P < 0.03). (B) Representative image showing a reverse correlation between expression of miR-205 and jagged1. Scale bars: 25 μm. S, stroma, T, tumor. (C) Diagram showing the promoter regions of MIR205 with the putative HES1 response elements (HES1-RE). (D) ChIP-PCR showing the percentage of the bound chromatin/input chromatin using HES1 antibody targeting HES1-binding elements (A and B) in BT549 breast cancer cells transfected with control or HES1 siRNA. IgG was used as a negative control (n = 3, *P < 0.05). (E) miR-205/mRNA expression levels of BT549 cells transfected with control or HES1 siRNA (n = 3, *P < 0.05). (F) Cell morphology of MCF12A cells stably expressing shRNA of the control vector (sh-Vec) and miR-205 (sh–miR-205). Scale bar: 20 μm. (G) miRNA and mRNA expression and (H) protein expression levels of sh-Vec and sh–miR-205–MCF12A cells. (I) The percentage of the CD24–CD44+ population (lower right quadrant) in sh-Vec and sh–miR-205 cells (n = 3, *P < 0.05). (J) The number of forming spheres per 1,000 cells generated from sh-Vec and sh–miR-205–MCF12A cells (n = 3, *P < 0.05). Scale bars: 100 μm, Error bars denote mean ± SD.
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