We aim to understand the contribution of endothelial cells and the angiogenic switch to support expansion of indolent latent metastatic cells. We will determine how endothelial cells are organized within latent metastasis by focusing on genomic, transcription and translation changes associated with overt metastasis. We will test several functions that support metastasis to identify where, when and how endothelial cells contribute to support exit from latency. To establish the contribution of endothelial cells in attenuating or supporting the expansion of latent metastasis, we will use a series of genetically engineered mouse models with reduced and enhanced angiogenesis through the manipulation of the PI3K pathway specifically in the endothelium. This will be back-crossed in Balb/c Nude athymic mice (FOXN1nu) background to subsequently introduce a series of human breast cancer latent metastasis models. Next, we will screen for communication signals and gene expression patterns among cancer and endothelial populations. Subsequent mechanistic analysis will be performed to understand the molecular dependencies among the cellular populations. Finally, confocal microscopy of in bone events will be performed post intra iliac injection and bone growth in vitro.