期刊
CANCER RESEARCH
卷 74, 期 20, 页码 5746-5757出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-13-2563
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资金
- National Basic Research Program of China (973 Program) [2010CB529403]
- National Natural Science Foundation of China [81071771, 30930103, 30725035, 81101631, 81101606]
- National Science and Technology Major Program [2011ZX09102-010-02]
- Natural Science Foundation Project of CQ CSTC [CSTC2012JJA10124]
- Intramural Research Program of the National Cancer Institute, NIH
Breast cancer stem-like cells (BCSC) are crucial for metastasis but the underlying mechanisms remain elusive. Here, we report that tumor-infiltrating natural killer (NK) cells failed to limit metastasis and were not associated with improved therapeutic outcome of BCSC-rich breast cancer. Primary BCSCs were resistant to cytotoxicity mediated by autologous/allogeneic NK cells due to reduced expression of MICA and MICB, two ligands for the stimulatory NK cell receptor NKG2D. Furthermore, the downregulation of MICA/MICB in BCSCs was mediated by aberrantly expressed oncogenic miR20a, which promoted the resistance of BCSC to NK cell cytotoxicity and resultant lung metastasis. The breast cancer cell differentiation-inducing agent, all-trans retinoic acid, restored the miR20a-MICA/MICB axis and sensitized BCSC to NK cell-mediated killing, thereby reducing immune escape-associated BCSC metastasis. Together, our findings reveal a novel mechanism for immune escape of human BCSC and identify the miR20a-MICA/MICB signaling axis as a therapeutic target to limit metastatic breast cancer. (C) 2014 AACR.
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