Tumor Suppressor Role of ARID1A

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DESCRIPTION (provided by applicant): The main objective of this study is to demonstrate the tumor suppressor role of ARID1A in the pathogenesis of endometrium-related cancer. ARID1A (BAF250A), a gene participating in the formation of a BRG1 SWI/SNF chromatin remodeling complex, has emerged as a potential tumor suppressor because we have recently demonstrated frequent somatic mutations of ARID1A in 46%-57% of ovarian clear cell carcinomas, 40% of uterine endometrioid carcinomas and 30% of ovarian endometrioid carcinomas. In our studies, the vast majority of the mutations are either the out-of-frame insertion/deletion type causing frameshift or nonsense mutations. Both mutation patterns are characteristic of classical tumor suppressor genes. Like other chromatin remodeling factors, ARID1A/BRG1 complex plays an important role in regulating transcriptional activity among many other cellular functions. Thus, we hypothesize that ARID1A is a tumor suppressor of which inactivating mutations contribute to the development of endometrium-related carcinoma by facilitating transcription of a set of cancer- related genes. To test this hypothesis, we propose three specific aims. To test the above hypotheses, we propose the following specific aims: Aim 1: Demonstrate the tumor suppressive effects of wild-type ARID1A. Aim 2: Investigate Validate and characterize candidate ARID1A-regulated genes. Aim 3: Analyze ARID1A in- frame deletion mutants to reveal a novel mechanism in regulating the steady-state protein levels of ARID1A. The results from this study will address several critical questions centering the roles of ARID1A in cancer biology and should have implication for translational cancer research.