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.