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.
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