Our overall goal has been to characterize seven LPB-Tag transgenic animal models for prostate cancer, collectively referred to as the LADY model. Our LADY models differ from other SV40-early region models since our deletion construct of the early region results in the expression only of the large T-antigen. Using these models, we have identified a number of pathological changes that accompany progression. The LADY models develop high grade prostatic epithelial and local invasive cancer but metastasis rarely develop in intact mice. Six of these models rarely develop neuroendocrine (NE) cancer in intact mice but after castration and tumor regression, regrowing tumors are NE cancers. This observation is similar to the increase in NE differentiation that accompanies failure to hormonal therapy in prostate cancer patients. One of the seven models, 12T-10, develops a NE tumor in intact mice. Our progress report identifies genes that are important in the initiation of prostatic intraepithelial neoplasia (PIN), cancer, and progression to metastatic cancer. Based on our discoveries, our central HYPOTHESIS for this application is that altered gene expression contributes to prostate tumorigenesis and metastasis. Our goals are to select candidate genes that are altered in a temporal order from the initiation of prostatic intraepithelial neoplasia (PIN) to metastatic prostate cancer; and to test the functional significance of these candidate genes as critically involved in tumor progression. Therefore, the central hypothesis can be divided into two specific hypotheses: 1) Correlating specific genetic events in a temporal manner will identify the sequential changes that are critical for tumor progression, and 2) The development of a neuroendocrine phenotype is an important late stage event in prostate tumor progression. The following three specific aims are proposed this continuing renewal: I) Analysis of microarray expression data during prostate tumor progression; II) To test candidate gene function during tumor progression, and III) To determine the pathways responsible for NE differentiation during prostate cancer progression. ? ? ?
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