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Although Notch signaling Is deregulated In prostate cancer, the role of this pathway In disease development and progression Is not fully understood. Here, we analyzed 2 human prostate cancer data sets and found that higher Notch signaling correlates with increased metastatic potential and worse disease survival rates. We used the Pten-null mouse prostate cancer model to investigate the function of Notch signaling in the initiation and progression of prostate cancer. Disruption of the transcription factor RBPJ in Pten-null mice revealed that endogenous canonical Notch signaling is not required for disease initiation and progression. However, augmentation of Notch activity in this model promoted both proliferation and apoptosis of prostate epithelial cells, which collectively reduced the primary tumor burden. The increase in cellular apoptosis was linked to DNA damage-induced p53 activation. Despite a reduced primary tumor burden, Notch activation in Pten-null mice promoted epithelial-mesenchymal transition and FOXC2-dependent tumor metastases but did not confer resistance to androgen deprivation. Notch activation also resulted in transformation of seminal vesicle epithelial cells in Pten-null mice. Our study highlights a multifaceted role for Notch signaling in distinct aspects of prostate cancer biology and supports Notch as a potential therapeutic target for metastatic prostate cancer., Introduction Notch is an evolutionarily conserved signaling pathway that is crucial for tissue development and homeostasis (1, 2). Deregulation of Notch signaling has been shown to play critical roles in [...]