In 2012, breast cancer (BC) accounted for 25% of all cancer cases worldwide and 15% of all cancer deaths among females.1 Late-stage BC is often associated with an immunosuppressive microenvironment and lacks of antitumor immune responses. Natural killer (NK) cells mediate direct cytotoxic activity against tumor cells and provide an early host defense against the transformed cells.2 NKG2D is one of the most important NK cell-activating receptors, which is also expressed on a subset of CD8+ T cells, γ/δ T cells, NK1.1+ T cells and lymphokine-activated killer (LAK) cells.3, 4, 5 Ligands for NKG2D receptors (NKG2DLs) comprise major histocompatibility complex class I chain-related proteins A and B (MICA/B) and unique long 16 (UL16) binding proteins 1–6 (ULBP1–6).6 NKG2D–NKG2DL stimulation of NK cells leads to strong activation and tumor cell rejection.7, 8, 9 However, malignant cells decrease their surface expression of NKG2DLs through downregulation and/or internalization10 as well as the shedding of NKG2DL extracellular domains.11 The downregulation of NKG2DL prevents the detection of malignant cells by immune cells, although the underlying mechanisms remain unclear.