It is proposed to characterize an invasive androgen-repressed and flutamide-stimulated phenotype in an ARCaP model of human prostate cancer metastasis. The PI hypothesizes that androgen repression is a central pathway for prostate cancer progression, and its acquisition is often accompanied by the development of androgenindependent, invasive and lethal disease. The metastatic profile of ARCaP cells in athymic mice resembles that of men who die of this disease. ARCaP's unique profile of metastasis and its ability to produce marked osteoblastic reactions provide an opportunity to define the biology and molecular mechanism associated with androgen repression and invasiveness in this tumor model. It is proposed that an imbalance of androgen receptor (AR) and its co-factors may be the molecular basis of aberrant androgen regulation of prostate cancer cell growth and gene expression. Such interaction may impact on the interaction between prostate cancer cells and bone stromal cells and/or bone matrix proteins, which could contribute to tumor invasion, metastasis and osteoblastic reaction. The following specific aims will be studied:
Specific Aim 1 : To characterize the molecular mechanism of AR regulation in growth, gene expression, and metastasis of ARCaP cells and tumors. We propose to identify, clone, and characterize genes encoding cofactors that may interact with AR. The effects of varying levels of AR and its co-factors on growth, gene expression, and the attachment, migration, and invasion of ARCaP cells in vitro and tumor metastasis in vivo will be evaluated.
Specific Aim 2 : To characterize the interaction between ARCaP cells and the bone matrix proteins osteopontin and vitronectin, based on an in vitro cell coculture model and an in vivo animal model. The roles of AR and its co-factors in mediating androgen and flutamide effects on cell attachment, migration, and invasion onto bone matrix proteins will be evaluated in vitro. The efficacy of drugs and antibodies that may block AMP cell interaction with bone matrix proteins and bone stromal cells will be tested both in vitro and in vivo with biomarker assessment. The ARCaP model may allow definition of the molecular basis of prostate cancer progression to androgen independence and expression of invasive and bone-homing phenotypes.
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