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BRG1: LUNG CANCER LEANNA BROOKS LUNG CANCER WHAT DOES THIS HAVE TO DO WITH BRG1? • LOH in chromosome 19 is frequent in NSLC tumors • BRG1 is very frequently inactivated in lung tumors. (as many as 1/3 of NSCLC cell lines have mutations in BRG1) • Mutations include frameshifts, nonsense or missense mutations. • Patients whose tumors are missing BRG1 have a worse prognosis • BRG1 mutations have also been found in pancreatic, prostate, breast and colon cancer cell lines • The mutations result in a truncated protein SWI/SNF CHROMATIN REMODELING COMPLEX • Activates (or deactivates) transcription by changing the structure of chromosomes; changing their affinity for transcription factors • ATP dependent • Critical for differentiation and proliferation • BRG1 is the ATPase – it provides the energy needed to carry out this function MOUSE EXPERIMENTS • Cre-Pos (black) = BRG1 inactivated • Cre-Neg (white) = control • Heterozygotes show more tumors, while homozygotes for BRG1 inactivation do not • Heterozygote inactivation of BRG1 leads to larger tumors (and worse prognosis) BRG1 DOWN-REGULATES MYC RESOURCES • Fukuoka, J, Fujii,T, Shih, JH, et al. (2004). “Chromatin Remodeling Factors and BRM/BRG1 Expression as Prognostic Indicators in Non-Small Cell Lung Cancer.” Clinical Cancer Research, 10: 4314-4324. • Glaros, S, Cirrincione, GM, Palanca, A, et al. (2008). “Targeted Knockout of BRG1 Potentiates Lung Cancer Development”. The Journal of Cancer Research, 68: 36893696. • “Non-Small Cell Lung Cancer Treatment” National Cancer Institute. Web. 26 Mar. 2015. <http://www.cancer.gov/cancertopics/pdq/treatment/non-small-celllung/Patient/page4>. • Reisman, D, and Thompson, EA. (2009). “The SWI/SNF complex and cancer”. Oncogene: 28, 1653-1668. • Rodrigues-Nieto, S, and Sanchez-Cespedes, M. (2009). “BRG1 and LKB1: tales of two tumor suppressor genes on chromosome 19p and lung cancer”. Carcinogenesis: 30, 547-554. • Romero, OA, Setien, F, John, S, et al. (2012). “The tumor suppressor and chromatinremodeling factor BRG1 antagonizes Myc activity and promotes cell differentiation in human cancer”. EMBO Molecular Medicine, 4: 603-616. • “What are the key statistics about lung cancer”. Web. 15 Mar. 2015. < http:// www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-celllung-cancer-key-statistics>. • Wu, JI. (2012). “Diverse functions of ATP-dependent chromatin remodeling complexes in development and cancer.” Acta Biochimica Biophys Sin, 44: 54-69.