Molecular and Cellular Pathobiology Metastatic Consequences of Immune Escape from NK Cell Cytotoxicity by Human Breast Cancer Stem Cells

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 stimulatoryNKcell receptorNKG2D. Furthermore, the downregulation ofMICA/MICB inBCSCswasmediated 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. Cancer Res; 74(20); 5746–57. 2014 AACR.