Impact of BRG1 Loss in Lung Cancer Development

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DESCRIPTION (provided by applicant): SWI/SNF is an important chromatin remodeling complex that is intimately involved in gene expression and regulates a variety of cell signaling pathways. This complex has been functionally linked to differentiation, development, and growth control. As it plays an integral role in such key cellular functions, it is not surprising that this complex is increasingly being recognized as a target for cancer development. Indeed, the SWI/SNF subunit BAF47 is known to be a bona fide tumor suppressor involved in the genesis of certain sarcomas, and when inactivated in mice, it is highly tumorigenic. In lung cancer and in a variety of other solid tumor types, we have found that other SWI/SNF subunits, BRG1 and its paralogous counterpart BRM are commonly lost together. As these two subunits are contained in different complexes, their mutual inactivation assures the abrogation of the SWI/SNF complex in the tumors that harbor this defect. The impact of the loss of BRG1 and BRM, hence the inactivation of the SWI/SNF complex, is not yet completely understood. However, both Rb and P53 have been functionally linked to BRG1 and BRM in vitro, suggesting that the loss of these proteins might negatively impact these important antitumor proteins in vivo as well. Though p53- and Rb- mediated growth inhibition can be linked to the SWI/SNF complex, we do not yet know if loss of BRG1, BRM or both is required to abrogate the functions of these antitumor proteins. This is scientifically and clinically important to define in vivo, as p53 and Rb block early tumor development by a checkpoint process referred to as "oncogene-induced senescence." For preneoplastic cells to progress, it is now recognized that this critical checkpoint must be abrogated. We hypothesize that loss of BRG1 or BRM can facilitate tumor development by negatively impacting Rb and p53. Our preliminary data support this view, as inactivation of either BRG1 or BRM increases early tumor development in mice. As BRG1 and BRM have redundant functions, it is not yet known what the impact of loosing both BRG1 and BRM will be on tumor progression. We hypothesize that the inactivation of both proteins will be highly tumorigenic, similar to the targeted knock- out of BAF47, which inevitably abrogates both BRG1- and BRM-containing complexes. Thus, the focus of this proposal: 1) we will determine if BRG1, BRM or both is required to abrogate Rb and p53 growth inhibition in cell lines in which either BRG1 or BRM has been knocked down by shRNAi and dominant- negative approaches (Aims 1 & 2). 2) We will determine whether the loss of BRG1 alone in conjunction with BRM promotes tumor progression--the transition of adenomas into malignant adenocarcinomas in our murine carcinogen model system. 3) We will determine if inactivation of BRG1 and BRM precludes the need for these tumors to alter expression of p16/Rb, and p19/p53 genes (Aims 3 and 4).