The key molecular changes in prostate cancer (CaP) that lead to androgen-independence have not yet been elucidated. We have found that p53 mutations are common in this disease and our preliminary studies have shown that a number of these mutants have gained specific oncogenic functions. The effect of such mutations on tumor biology and patient outcome will be assessed in this grant proposal. Recently, the p53 pathway has been linked to the anti-apoptotic factor BAG-1L, which has additionally been shown to enhance the sensitivity of the androgen receptor (hAR) to its ligands. Thus, our hypothesis is that p53 alterations are central to the molecular changes leading to the progression of this disease.
The specific aims of this study are to understand the role that different p53 mutations play in the development of androgen independence and to discover how such mutations affect the prognosis of patients with CaP. In order to do this; 1) we will correlate patient outcome with the functional biology of different mutant p53 alleles. We will examine racial differences in the frequency of specific gain-of- function p53 alterations with the expectation that such differences may help explain the poorer prognosis of African American CaP patients. 2) We will test specific gain-of-function p53 mutants for their ability to form tumors in nude mice, as well as for their contributions to radiation resistance and for their effects on gene expression using Real-Time PCR and microarray studies. 3) We will show that certain gain-of-function mutant p53 alleles lead to androgen-independent growth through sensitization of the androgen receptor by BAG-1L. This will be accomplished by modifying the LNCaP cell line and examining its androgen-independent growth in vitro or in castrated nude mice. We will confirm these results by blocking BAG-1L activity using either antisense BAG-1L or a BAG-1L inhibitor. The results obtained during the period of this grant proposal will form the basis for future studies that should affect treatment strategies for this disease.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Special Emphasis Panel (ZRG1-UROL (01))
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Freeman, Colette S
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University of California Davis
Schools of Medicine
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Shi, Xu-Bao; Xue, Lingru; Shi, Donghua et al. (2011) Influence of short polyglutamine tracts and p160 coactivators on the transactivation of the androgen receptor. Cancer Biother Radiopharm 26:191-201
Shi, Xu-Bao; Xue, Lingru; Zou, June X et al. (2008) Prolonged androgen receptor loading onto chromatin and the efficient recruitment of p160 coactivators contribute to androgen-independent growth of prostate cancer cells. Prostate 68:1816-26
Shi, Xu-Bao; Xue, Lingru; Tepper, Clifford G et al. (2007) The oncogenic potential of a prostate cancer-derived androgen receptor mutant. Prostate 67:591-602
Tepper, Clifford G; Gregg, Jeffrey P; Shi, Xu-Bao et al. (2005) Profiling of gene expression changes caused by p53 gain-of-function mutant alleles in prostate cancer cells. Prostate 65:375-89
Shi, Xu-Bao; Ma, Ai-Hong; Tepper, Clifford G et al. (2004) Molecular alterations associated with LNCaP cell progression to androgen independence. Prostate 60:257-71
Shi, Xu-Bao; Gandour-Edwards, Regina; Beckett, Laurel A et al. (2004) A modified yeast assay used on archival samples of localized prostate cancer tissue improves the detection of p53 abnormalities and increases their predictive value. BJU Int 94:996-1002
Martel, Cynthia L; Gumerlock, Paul H; Meyers, Frederick J et al. (2003) Current strategies in the management of hormone refractory prostate cancer. Cancer Treat Rev 29:171-87
Nesslinger, Nancy J; Shi, Xu-Bao; deVere White, Ralph W (2003) Androgen-independent growth of LNCaP prostate cancer cells is mediated by gain-of-function mutant p53. Cancer Res 63:2228-33
Shi, Xu-Bao; Ma, Ai-Hong; Xia, Liang et al. (2002) Functional analysis of 44 mutant androgen receptors from human prostate cancer. Cancer Res 62:1496-502
Shi, Xu-Bao; Nesslinger, Nancy J; Deitch, Arline D et al. (2002) Complex functions of mutant p53 alleles from human prostate cancer. Prostate 51:59-72

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