期刊
AMERICAN JOURNAL OF PATHOLOGY
卷 183, 期 5, 页码 1688-1697出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2013.07.020
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资金
- Clinical, diagnostic and therapeutic implications of studies on breast cancer stem cells [PRINT 2008KTRN38]
- RFO funds
- Cornelia Pallotti and Roberto Pallotti Foundation
Cancer stem cell survival relies on the activation of inflammatory pathways, which is speculatively triggered by cell autonomous mechanisms or by microenvironmental stimuli. Here, we observed that hypoxic bone marrow stroma derived transforming growth factor-beta 1 promotes the growth of human breast cancer stem cells as mammospheres. The ensuing Slug-dependent serine 139 phosphorylation of the DNA damage sensor H2AX in breast cancer stem cells induces tumor necrosis factor-alpha and IL-8 mRNAs, whose stability is enhanced by cytoplasmic beta-catenin. beta-Catenin also up-regulates and binds miR-221, reducing the stability of the miR-221 targets Rad51 and ERcc mRNAs. Our data show that the Slug/beta-catenin dependent activation of DNA damage signaling triggered by the hypoxic microenvironment sustains the proinfLammatory phenotype of breast cancer stem cells.
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