DF/HCC Program Affiliation

Cancer Genetics
Cancer Cell Biology

Research Abstract

My laboratory is interested in the role of dysfunctional chromatin remodeling in the genesis of cancer. It is increasingly clear that epigenetic modifications play a critical role in the development of cancer. The Swi/Snf complex, which utilizes ATP hydrolysis to remodel chromatin, has a potent role in the genesis of cancer. Accumulating evidence has linked the Swi/Snf complex to both human cancer and other tumor suppressor pathways indicating that the complex has diverse roles in growth regulation and tumor suppression. Indeed, we have recently demonstrated a key role for Snf5, a core member of this complex, in tumor suppression in a novel mouse model. Inactivating mutations in the SNF5 gene result in aggressive cancers in children and a familial cancer predisposition syndrome. We hypothesize that Snf5 is a master regulator of gene expression via its effects on chromatin structure and seek to identify the mechanisms by which perturbation of this ATPase chromatin remodeling complex leads to cancer formation. Given the dramatic nature in which inactivation of Snf5, leads to cancer formation, complete characterization of this complex will lead to insights into tumorigenesis and may further suggest novel therapeutic strategies. Thus, we are using mouse modeling, molecular biological, and biochemical approaches to characterize this newly appreciated mechanism of tumor suppression.

Publications

• Tamayo P, Scanfeld D, Ebert BL, Gillette MA, Roberts CW, Mesirov JP.Metagene projection for cross-platform, cross-species characterization of global transcriptional states.Proc Natl Acad Sci U S A 2007 Apr 3;104(14):5959-64.
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• Sansam CG, Roberts CW.Epigenetics and cancer: altered chromatin remodeling via Snf5 loss leads to aberrant cell cycle regulation.Cell Cycle 2006 Mar;5(6):621-4.
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• Isakoff MS, Sansam CG, Tamayo P, Subramanian A, Evans JA, Fillmore CM, Wang X, Biegel JA, Pomeroy SL, Mesirov JP, Roberts CW.Inactivation of the Snf5 tumor suppressor stimulates cell cycle progression and cooperates with p53 loss in oncogenic transformati
  16301525
• Roberts CW, Orkin SH.The SWI/SNF complex--chromatin and cancer.Nat Rev Cancer 2004 Feb;4(2):133-42.
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• Roberts CW, Leroux MM, Fleming MD, Orkin SH.Highly penetrant, rapid tumorigenesis through conditional inversion of the tumor suppressor gene Snf5.Cancer Cell 2002 Nov;2(5):415-25.
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• Roberts CW, Galusha SA, McMenamin ME, Fletcher CD, Orkin SH.Haploinsufficiency of Snf5 (integrase interactor 1) predisposes to malignant rhabdoid tumors in mice.Proc Natl Acad Sci U S A 2000 Dec 5;97(25):13796-800.
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