期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 124, 期 7, 页码 3093-3106出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI73351
关键词
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资金
- Showalter Research Scholar grant [206793]
- Purdue University Center for Cancer Research [P30 CA023168]
- American Cancer Society Institutional Research grant [IRG 58-006-53]
- CPRIT Graduate Scholar Training Program at The University of Texas MD Anderson Cancer Center
- National Breast Cancer Foundation Inc.
- China Medical University Hospital Cancer Research Center of Excellence [MOHW103-TD-B-111-03]
- Stem Cell and Regenerative Medicine Frontier Research [NSC 102-2321-B-039-001]
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 sternness. 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.
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