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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National Cancer Institute (NCI)
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Special Emphasis Panel (ZRG1-ONC-L (03))
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Yassin, Rihab R,
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Emory University
Internal Medicine/Medicine
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Sun, Xiaodong; Li, Jie; Sica, Gabriel et al. (2013) Interruption of nuclear localization of ATBF1 during the histopathologic progression of head and neck squamous cell carcinoma. Head Neck 35:1007-14
Dong, Xue-Yuan; Fu, Xiaoying; Fan, Songqing et al. (2012) Oestrogen causes ATBF1 protein degradation through the oestrogen-responsive E3 ubiquitin ligase EFP. Biochem J 444:581-90
Su, Dan; Fu, Xiaoying; Fan, Songqing et al. (2012) Role of ERRF, a novel ER-related nuclear factor, in the growth control of ER-positive human breast cancer cells. Am J Pathol 180:1189-201
Dong, Xue-Yuan; Guo, Peng; Sun, Xiaodong et al. (2011) Estrogen up-regulates ATBF1 transcription but causes its protein degradation in estrogen receptor-alpha-positive breast cancer cells. J Biol Chem 286:13879-90
Dong, Xue-Yuan; Sun, Xiaodong; Guo, Peng et al. (2010) ATBF1 inhibits estrogen receptor (ER) function by selectively competing with AIB1 for binding to the ER in ER-positive breast cancer cells. J Biol Chem 285:32801-9
Dong, Xue-Yuan; Guo, Peng; Boyd, Jeff et al. (2009) Implication of snoRNA U50 in human breast cancer. J Genet Genomics 36:447-54
Chen, Ling; Zhu, Zhengmao; Sun, Xiaodong et al. (2009) Down-regulation of tumor suppressor gene FEZ1/LZTS1 in breast carcinoma involves promoter methylation and associates with metastasis. Breast Cancer Res Treat 116:471-8
Dong, Xue-Yuan; Rodriguez, Carmen; Guo, Peng et al. (2008) SnoRNA U50 is a candidate tumor-suppressor gene at 6q14.3 with a mutation associated with clinically significant prostate cancer. Hum Mol Genet 17:1031-42
Sun, Xiaodong; Zhou, Yingfa; Otto, Kristen B et al. (2007) Infrequent mutation of ATBF1 in human breast cancer. J Cancer Res Clin Oncol 133:103-5
Sun, Xiaodong; Chen, Ceshi; Vessella, Robert L et al. (2006) Microsatellite instability and mismatch repair target gene mutations in cell lines and xenografts of prostate cancer. Prostate 66:660-6

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