The microenvironment is known to be a central regulator of tumor biology. While the contribution of some stromal cells, such as cancer-associated fibroblasts or macrophages, has been well elucidated, the endothelial cells’ role, as regulators of cancer cell behavior, is still poorly investigated. Whereas tumor angiogenesis, involving endothelial cells, and promoting cancer progression, has been well characterized in its molecular portrait and mechanisms and provides the rational behind established modern cancer therapy (monoclonal antibodies, TKIs), still little is known about how endothelial cells, as components of the tumor microenvironment, can directly influence the behavior of cancer cells.  Endothelial cells modulate a diverse spectrum of pathophysiologic processes in normal tissues. Therefore they might offer a similar paracrine regulatory control in cancer biology.  Over the last years, using global gene expression analysis, we have started to characterize effects of tumor stromal cell interaction, specifically breast cancer fibroblastic stroma interaction, tumor osteoblast interaction and tumor endothelial interaction ¹. After establishing the methods and analysis tools, we characterized the diversity of tumor endothelial interaction. We described tumor endothelial interaction as a link between the C44+/CD24- stem cell like signature and highly aggressive, unfavorable prognostic breast carcinomas. Our results suggest the interaction of endothelial cells with tumor cells that express the CD44+/CD24- stem cell-like signature, which indicates a low proliferative potential, might explain the unexpected and paradoxical association of the CD44+/CD24- signature with highly proliferative tumors that have an unfavorable prognosis. To further characterize the functional effects and their associated molecular portraits of endothelial-cancer interaction we further focused on an in vitro model of SKBR3 breast cancer cells and human endothelial cells. We could show that endothelial cells growing in sparse conditions compared to dense, confluent, conditions, mimicking an activated endothelium, were able to influence SKBR3 breast cancer cells, by inducing epithelial-mesenchymal transition and increasing their migratory potential. Global gene expression analysis revealed a list of genes significantly associated with increased migratory potential such as WNT5A, PTGS1, CTSS, CD44, FN1, S100A7 etc. This effect is mediated by secreted factors in the endothelial supernatant, which are not yet characterized. The endothelial cells role in increasing tumor cell’s migratory potential is not yet well described. Therefore we now aim to a) Characterize the molecular signaling mechanisms of enhanced migratory potential by endothelial tumor interaction. B) Characterize and test the effects of the increased migratory potential due to cancer cell and endothelial cell interaction in vivo. C) Determine the expression of the molecules of interest in human breast cancer tissue samples and analyzes them as prognostic markers in breast cancer patients. With this approach we hope to find new therapeutic strategies involving the tumor endothelial cells, independent from anti-angiogenesis, as therapeutic targets and prognostic markers.