The present study reports the following novel findings: (1) high MICB expression may be an indicator of a good prognosis in BC; (2) members of the miR-17-92 cluster inversely regulate ULBP2 and MICA/B in BC cells, which influences the immunogenicity of BC; (3) miRNAs downregulate the expression of MICA/B by targeting the mRNA 3'-UTR and downregulate ULBP2 by inhibiting the MAPK/ERK signaling pathway; (4) the HDACis SAHA and VPA may increase the expression of MICA/B and ULBP2 by inhibiting the miR-17-92 cluster; and (5) SAHA and VPA cannot effectively increase the expression of NKG2DLs in normal breast cells. In conclusion, this study is the first to comprehensively assess the miRNA-mediated NKG2DL regulation in the context of BC (Figure 6g). Our results indicate that targeting miRNAs with antisense inhibitors or by HDACis might therefore represent a novel approach to increasing the immunogenicity of BC.