Clinical evidence indicates that ErbB-2 is overexpressed in late-stage prostate cancers, however there is controversy as to whether ErbB-2 plays a role in pre-neoplastic and benign prostate cancer. Clinical data demonstrated that the tumor suppressor gene pten (phosphatase and tensin homolog deleted on chromosome 10) is a phosphatase that inhibits PI3Kinase signaling and is one of the most frequently mutated genes identified in human prostate cancers. While ErbB-2 and Pten may therefore play important roles in prostate cancer progression, as may be predicted by the Knudsen hypothesis, no studies done to date have directly addressed this question in vivo. We have engineered mice that express an activated isoform of ErbB-2. These mice model enhanced growth factor signaling in the prostate, which was sufficient to induce neoplastic progression but not adenocarcinoma. We believe therefore that in the normal prostate gland, negative regulatory mechanisms exist that afford protection against cancer progression. Hypothesis: The combined dysregulation of both the MAPK and PI3K pathways is required for prostate cancer progression and that cross-talk between ErbB-2 signaling and Pten function plays a critical role in this process. We propose that ErbB-2 induced transformation requires the dysregulation of PI3Kinase-regulated target genes that are normally inhibited by the tumor suppressor, Pten. We will define the roles of ErbB-2, Pten, the MAPK and the PI3K signaling cascades in regulating key target genes, including cyclin D1, in human prostate cancer cell lines, in vitro. We will identify key signaling pathways activated by ErbB-2 that may enable us to target specific pathways or critical target genes for future prostate cancer intervention.