The biology of prostate cancer is poorly understood, and it is still an important task to identify and characterize the genes whose alterations contribute to prostate cancer. Our overall hypothesis is that frequently deleted chromosomal regions harbor tumor suppressor genes whose inactivation through deletion, gene mutation, and/or loss of expression is a common cause of carcinogenesis. This hypothesis has been validated by knockout mouse studies for PTEN from 10q23, p27 from 12p12, and NKX3-1 from 8p21. With the support of the previous grant, we performed deletion mapping and gene identification for three chromosomal regions, 13q14, 6q15, and 16q22, each of which is frequently deleted in human prostate cancer. Our genetic and functional studies have established FOXO1A transcription factor, RNU50 snoRNA, and ATBF1 transcription factor as reasonable candidates for tumor suppressor genes at the 13q14, 6q15, and 16q22 regions respectively. The ATBF1 gene at 16q22 may be the most interesting, because it is not only deleted and downregulated, it also has frequent somatic mutations in prostate cancer (Sun et al., Nature Genetics 37:407-412, 2005). Furthermore, ectopic expression of ATBF1 suppressed and knockdown of ATBF1 enhanced cell proliferation or survival. Published studies suggest that ATBF1 interacts with other molecules to regulate gene expression. We therefore hypothesize that ATBF1 is a bona fide tumor suppressor gene whose inactivation leads to prostate cancer through altered interactions with other molecules regulating cell proliferation and gene expression. We will test this hypothesis in three specific aims. 1) Functionally evaluate ATBF1 mutations using in vitro and in vivo systems. We will first determine if mutations detected in human prostate cancers impair ATBF1 structure and function in vitro. We will then examine if inactivation of ATBF1 in mice causes prostate cancer. 2) Assess the effect of ATBF1 alterations on different clinical and pathological aspects of prostate cancer. 3) Test if ATBF1 interacts with other molecules to regulate gene expression, and identify what molecules are involved in the interaction and what genes are regulated by the interaction. These studies should clarify the role of ATBF1 in prostate cancer, establish a mouse prostate cancer model that is relevant to human disease, and uncover a new pathway underlying prostatic carcinogenesis. They may also present ATBF1 as a useful biomarker. ? ? ?
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