The Roberts 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 tumor suppressor role.  Several of its subunits are specifically mutated in a variety of lethal human cancers including those of lung and breast as well as childhood cancers.  Accumulating evidence has revealed a role for the complex in epigenetic regulation via nucleosome remodeling based control of lineage-specific transcription.  Indeed, we have demonstrated key roles for SNF5, a core member of this complex, in tumor suppression using genetically engineered mouse models. 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 drives cancer formation, characterization of this complex will lead to insights into the mechanisms of tumorigenesis. Thus, we are using mouse modeling combined with molecular, cellular and biochemical approaches to characterize this newly appreciated mechanism of tumor suppression and to identify novel therapeutic targets.