Metastatic, hormone independent prostate cancer (CaP) is incurable. The goal of this multidisciplinary Program Project is to elucidate the signal transduction mechanisms that underlie the stepwise events associated with progression of CaP from a localized and androgen sensitive tumor to a disseminated and androgen independent one. The Program brings together productive and experienced investigators with complementary expertise relevant to the stated goal of the Program and backgrounds in signal transduction (J. T. Parsons, S. J. Parsons, Weber), nuclear receptor biology (Paschal), bone biology (Guise), human prostate cancer pathology (Frierson), biostatistics (Conaway) and basic and clinical prostate cancer metastasis research (Theodorescu). In Project 1, Theodorescu and J. T. Parsons propose to evaluate the roles of VEGF, FAK and Rap in CaP progression and metastasis to bone; Project 2, S. J. Parsons studies the regulation of neuroendocrine cell growth within advanced prostate cancers and the impact of such cells on overall tumor dependence on androgen; Project 3, M. Weber studies Ras-mediated signaling cascades as they affect ligand hypersensitive androgen receptor activity; Project 4, Paschal proposes to study the relationship between androgen receptor activation and the control of its nuclear localization. This interactive Program relies heavily on synergistic technical and scientific expertise from all investigators. The productivity of individual Projects is catalyzed by highly interactive Cores led by Theodorescu (Administrative Core A) which integrates the participation of M. Conaway an expert biostatistician; Guise (Cell, Animal and Imaging Core B) who has extensive experience in bone histology and histomorphometry and who is familiar with the biology of prostate cancer and the xenograft models used in prostate cancer research as well as their in vivo imaging; Frierson, (Tissue Analysis Core C), an expert surgical pathologist who specializes in CaP. Together, these Projects and Cores integrate diverse skills and expertise to focus on areas fundamental to our understanding tumor progression in CaP, with the objective of accelerating progress in developing a cure for this devastating disease.