After successful local control, 35% of patients with prostate cancer (PC) experience progression. KLF6 is a transcription factor with growth inhibitory activity through induction of p21 (Waf1/Cip1). We recently identified KLF6 as a tumor suppressor gene mutated in 55% of primary PC. KLF6 mutants failed to induce p21 and to suppress growth of PC cells in culture. We postulate that KLF6 mutations confer PC cells with increased proliferative potential and as a result the frequency of KLF6 mutants will be higher in advanced disease and that, by suppressing p21, they may facilitate AI progression. The effect of KLF6 mutations on its expression and its ability to suppress p21 in vivo is unknown. Likewise, its relation to the androgen receptor (AR) which can also suppress p21 is unknown. Therefore, presence, frequency and type of KLF6 mutations may be linked to specific stages in PC progression providing a new biological marker for this disease. Our goals are 1. To determine the frequency and type of KLF6 mutations in benign prostate, pre-invasive lesions (PIN), invasive carcinoma and metastases and to assess the efficacy of KLF6 mutation as diagnostic and prognostic molecular marker of outcome in PC patients. We propose to perform mutation analysis of 480 laser captured specimens, and establish the frequency and type of KLF6 mutations. We will compare frequency of mutations between normal, primary and metastatic tissues. KLF6 mutations in the primary will be correlated with clinical risk factors, time to PSA failure and occult metastasis to lymph nodes; in bone marrow metastasis with AR mutations, time to PSA failure and survival. 2. To study the effect of KLF6 mutations on its expression and function in relation to p21 and AR. Using quantitative real time PCR and immunohistochemistry, the level of KLF6, p21 and AR mRNA and protein in normal epithelium, mutant and non-mutant primary, and bone marrow metastasis will be determined and compared. These studies will establish the value of KLF6 as a diagnostic and prognostic molecular marker for outcome and the biological effect of mutations on progression. ? ?
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