Chromatin remodeling complexes play a key role in the regulation of cellular transcription by modulating access of proteins to DNA. In human neoplasia, alterations in components of chromatin remodeling complexes can impact many hallmarks of human cancers including cell cycle regulation, cellular differentiation, DNA methylation, imprinting and gene transcription. Several recent reports have demonstrated loss of function of components of the SWI/SNF (mating type switch/sucrose nonfermenting) chromatin remodeling complex in human and mouse cancers. Absence of the SWI2 homologue, BRG1, leads to a loss of the RB tumor suppressor protein's ability to control the cell cycle. Loss of SNF5/INI1/BAF47 function underlies the development of most rhabdoid tumors. Our laboratory has found that over 20% of human adenocarcinoma cell lines have lost expression of at least one member of the SWI/SNF complex. We have also found mutations and deletions of the SNF5 gene in human rhabdoid tumor cell lines and primary rhabdomyosarcomas. How the loss of different components of the SWI/SNF complex contributes to neoplastic transformation remains an open and important question. My laboratory concentrates on addressing this question by the combined use of biological, biochemical and mouse models for SWI/SNF complex function. We have focused our efforts on four components of complex including BRG1, BRM, BAF57, and SNF5/INI1. We hypothesize that alterations in the activities of components of the SWI/SNF complex contribute to human and mouse tumor development by altering the regulation of key cell cycle components. We are testing this hypothesis by determining the mechanisms underlying BAF57- and SNF5-induced inhibition of growth upon re-expression in deficient tumor cell lines. We are also carrying out structure/function analyses of these proteins by biological and biochemical assays. We are also assessing the consequences of the loss of each component on normal and neoplastic development by the production of a genetically engineered mouse. Altered SWI/SNF function could impact upon several aspects of human tumor etiology. For example, we have shown that the SWI/SNF complex regulates CD44 expression. Loss of CD44 expression in human tumors often correlates with poorer prognosis. SWI/SNF complex loss may render tumor cells resistant to the lethal effects of cis-platinum. Therefore, loss of SWI/SNF function may negatively impact treatment modalities used for the spread of metastatic adenocarcinomas and may provide an informative indicator of therapeutic progress. Finally, considering that the SWI/SNF complex acts as a global regulator of transcription, human tumors that lose its function may possess a greater likelihood for progression and metastases due to a higher potential for altered gene expression.