Research Overview

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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. At least six SWI/SNF subuntis have recently been found to be recurrently and frequently mutated in a variety of human cancers, including in highly pediatric cancers called malignant rhabdoid tumors as well as in substantial subsets of lung, breast, prostate, colorectal, ovarian, pancreas, stomach, liver, kidney, and bladder cancers. 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, wWe have recently demonstrated the functional significance of these mutations by generating mice carrying conditional mutations in a key role for Snf5, a core member of this complex, and finding that 100% of these mice develop cancer, with a median onset of only 11 weeks. This rate is remarkably rapid for the inactivation of a single gene, and is indeed twice as fast as P53 deficient mice develop cancer. 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 are now focused upon elucidating the mechanism by which mutation of SWI/SNF subunits drives cancer growth with a goal of identifying new ways to therapeutically intervene in these cancers. 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, cComplete characterization of this complex will lead to insights into tumorigenesis and may should identify 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.

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  • Altered Chromatin Remodeling and Epigenetics in Cancer

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