Cancers adopt diverse strategies to safeguard their survival. The stimulatory NKG2D lymphocyte receptor on natural killer (NK) cells and CD8 T cells and its tumor-associated ligands are important mediators in the immune surveillance of cancer. With advanced human tumors, however, persistent NKG2D ligand expression favors tumor progression, which has been ascribed to immune evasion. In a surprising conceptual twist, cancer cells themselves express NKG2D receptors and may thus exploit the presence of its ligands for self stimulation of tumor growth. Variable proportions of breast, ovarian, prostate and colon cancer cells express surface NKG2D together with its DAP10 signaling adaptor. Ligand engagement of NKG2D activates oncogenic signaling cascades, thereby stimulating cellular bioenergetic metabolism and proliferation. Above- threshold expression of NKG2D-DAP10 in a ligand-bearing tumor line induces key transcription factors and differentiation changes characteristic of the epithelial-mesenchymal transition (EMT), a cellular reprogramming process that leads to increased cancer cell motility and dissemination. As EMT is interrelated with the acquisition of cancer stem cell traits, NKG2D may be associated with these self-renewing cells that are considered main culprits of failed cancer therapies. Altogether, these findings challenge translational concepts in tumor immunology as cancer cells may co-opt NKG2D expression for their own benefit. However, the functional scope of NKG2D in tumorigenesis is insufficiently defined as critical issues regarding its role in EMT reprogramming and induction of stem cell traits are unexplored. Moreover, direct in vivo evidence for pathophysiological significance is missing thus far, which will be obtained in breast cancer mouse model studies of primary and metastatic tumorgenicity. These study objectives aim to bridge profound knowledge gaps at the interface between tumor immunology and cancer biology. They will complement clinical studies proposed to test for associations between frequencies of NKG2D positive cancer cells, disease-specific clinical-pathological tumor parameters, and outcome in large cohorts of patients with primary invasive breast cancer or epithelial ovarian cancer. Overall, this research program will advance understanding of cancer pathophysiology and establish a novel mechanism that promotes tumor autonomy. The results may have profound biomedical and clinical implications, especially in regard to translational approaches targeting NKG2D or its ligands for cancer therapy.