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L E A N N A B R O O K S
BRG1: LUNG CANCER
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: 3689-3696.
• “Non-Small Cell Lung Cancer Treatment” National Cancer Institute. Web. 26 Mar. 2015. <http://www.cancer.gov/cancertopics/pdq/treatment/non-small-cell-lung/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 chromatin-remodeling 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-cell-lung-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.