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Identification and characterization of genes associated with the hormonal progression of prostate cancer Quayle, Steven Norman

Abstract

Prostate cancer is the most frequently diagnosed cancer as well as the second leading cause of cancer deaths among American men. Androgen deprivation therapy for patients with advanced prostate cancer inevitably fails as the disease progresses to the terminal, hormone-refractory stage. At the present time no effective therapies can be offered to patients in this stage of the disease. Currently, the molecular alterations that contribute to the development of hormone-refractory disease are poorly understood. Here, suppression subtractive hybridization was performed to identify genes of interest in a model of progression of prostate cancer to androgen independence. Subtractive hybridization identified a number of novel transcripts that had previously not been described. From this work it was hypothesized that (1) the novel transcripts identified may prove informative in the clinical management of prostate cancer, and (2) that the known genes identified may function in the progression of prostate cancer. One of these novel transcripts was shown to encode a truncated splice variant of the transmembrane protein TMEFF2. TMEFF2 is specifically expressed in the prostate and the brain, and other groups have developed antibodies targeting TMEFF2 for the treatment of metastatic prostate cancer. The isoform described here, TMEFF2-S, encodes a protein secreted by prostate cancer cells. Being a prostate-specific, secreted protein, TMEFF2-S may prove informative in predicting patient outcome. Additionally, the secretion of TMEFF2-S may influence the effectiveness of immunotherapy approaches targeting TMEFF2. Subtractive hybridization, together with other high-throughput screening techniques, also led to the examination of the potential functions of the 14-3-3 family of proteins in the progression of prostate cancer. These experiments demonstrated that 14-3-3 sigma specifically increased the activity of the androgen receptor in the absence of androgens. Thus, this finding may have implications for patients undergoing androgen deprivation therapy. Further studies will be required to determine if 14-3-3 sigma is active in a subset of patients with hormone refractory prostate cancer. If so, its role in activating the androgen receptor may potentially be targeted for the development of novel therapeutics for the treatment of hormone-refractory disease.

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