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4504 Introduction and Objective: Prostate cancer (PCa) bone metastasis often present in patients after a long latent period. Dormant cancer cells in contact with bone stromal cells can be reactivated under certain pathophysiologic conditions. We characterized novel molecular pathways leading to PCa bone metastasis in animal models. Methods: Tissue microarrays of normal (4), PIN (13), benign (22), primary (19) PCa and PCa bone metastasis (58) were analyzed by IHC for the expression of β2-microglobulin (β2-M), a novel growth factor and signaling molecule, focal adhesion kinase (FAK), a key cell adhesion molecule, LIV-1, a zinc transporter involved in epithelial to mesenchymal transition, BDNF, a chemokine, and heparanase (HPSE), a heparan sulfate (HS) degrading enzyme. IHC was scored blindly by one pathologist. Data were analyzed by Kruskal-Wallis test for p-value and logistic regression analysis to differentiate Gleason scores. Results: PCa cells with mitochondrial DNA mutations or activated by β2-M provoked consistently higher levels of reactive oxygen species (ROS) production. ROS stimulated HS proteoglycan, perlecan, expression and augmented PCa cell growth in bone microenvironment. Downstream targets of ROS, HS/perlecan and β2-M signaling were identified: FAK, LIV-1, and BDNF. Results showed that β2-M (p