Emerging data implicate the SWI/SNF chromatin remodeling complex as a major tumor suppressor. Over the past [two years], numerous cancer genome sequencing studies have revealed that at least six subunits of the complex are specifically inactivated at high frequency in a variety of human cancers including those of ovary, breast, kidney, lung, pancreas, uterus, bladder, stomach, colon, liver [and skin]. The SWI/SNF complex includes both core and lineage-specific subunits and utilizes the energy of ATP to modulate chromatin structure. My laboratory has demonstrated a potent and bona fide tumor suppressor role for one of the subunits through generation of a knockout mouse model. Providing some insight into mechanism, we have recently established the existence of epigenetic antagonism between SWI/SNF and Polycomb complexes. However, the contributions of the SWI/SNF complex to chromatin structure in vivo and the reasons why each subunit is associated with distinct cancer spectra remain poorly understood. Given the unique chromatin targeting and modification domains found in each subunit, we hypothesize that oncogenesis occurs due to differential mistargeting of residual SWI/SNF complexes and impairment of their chromatin remodeling activity. We further hypothesize that SWI/SNF subunit mutations cause disruption of lineage-specific gene expression programs arising from imbalanced epigenetic antagonism with the Polycomb PRC2 complex. Via the following specific aims, our goals are to determine how the subunits of the SWI/SNF complex contribute to chromatin structure, to establish the mechanism by which mutation of the tumor suppressor subunits drives cancer formation, to determine the extent of epigenetic antagonism between the tumor suppressor subunits and the PRC2 complex, and to identify novel and effective therapeutic targets for SWI/SNF mutant cancers: Aim 1: How does loss of individual SWI/SNF tumor suppressor subunits affect the DNA binding, chromatin remodeling activity, and integrity of the SWI/SNF complex, and how does their loss affect gene expression? Aim 2: What is the role of the residual SWI/SNF complex in cancers driven by mutation of SWI/SNF tumor suppressor subunits? Aim 3: What is the relationship between Polycomb complexes and cancers that are driven by SWI/SNF mutations? Significance: Given the increasingly wide spectrum of cancers being found to contain mutations in SWI/SNF subunits, the complex now emerges as having major relevance for human disease. Testing our hypotheses via the proposed specific aims has the potential to elucidate the function of the normal SWI/SNF complex, establish the mechanisms by which mutation of SWI/SNF tumor suppressor subunits drive cancer formation, and identify therapeutic targets for the wide variety of SWI/SNF mutant cancers.