Malignant rhabdoid tumor (MRT) is an aggressive, highly lethal cancer that strikes young children. Tumors occur in various locations including kidney, brain, and soft tissues. Despite intensive therapy, 80 percent of affected children die, often within 1 year of diagnosis. The vast majority of MRTs have sustained bi-allelic inactivating mutations of the hSNF5/INI1 gene, suggesting that SNF5 may act as a tumor suppressor. Supporting this idea is the fact that 15 percent of children with MRT have somatic mutations in one allele of SNF5 and loss of the remaining allele in their tumors. SNF5 is a core member of the SWI/SNF chromatin remodeling complex, which is required for regulated expression of a subset of genes. In humans, SNF5 binds to HIV integrase and stimulates integration of HIV into human DNA. Studies have also shown that SNF5 binds to EBNA, MLL/ALL- 1, trithorax, and c-MYC and stimulates transcription by these factors. Another member of the SWI/SNF complex, Brg1, directly interacts with pRb and is required for Rb mediated cell cycle arrest. Haploinsufficiency of Brg1 predisposes mice to tumor formation and Brg1 is deficient in several breast cancer cell lines. Together, these data suggest a widespread role for SWI/SNF in tumor suppression. While it is clear that SNF5 and SWI/SNF are involved in tumor suppression, chromatin remodeling and transcriptional activation, their mechanism of action and the relationship between these processes is not clear. We have used gene targeting to inactivate SNF5 in mice. Absence of SNF5 results in embryonic lethality while haploinsufficiency results in 15 percent of mice developing tumors histologically indistinguishable from human MRT.
The specific aims of the proposed project are to generate SNF5 deficient cells to determine the function of SNF5 in growth regulation and oncogenic transformation. Second, to improve the MRT model by generating conditionally targeted mice that develop MRT with high penetrance in locations where human tumors occur. Third, to identify genes downstream of SNF5 through use of conditionally targeted cells in DNA micro-array analysis. Lastly, to investigate the function of SNF5 in transcriptional regulation by analysis of SNF5 deficient cells using in vitro transcriptional assays. Since SNF5 is an invariant subunit present in all SWI/SNF complexes, elucidation of its function will provide insight into a newly appreciated mechanism of tumor suppression and may identify new targets for therapeutic intervention against a lethal pediatric cancer. This proposal directly addresses scientific priorities identified by the BT-PRG arm of the NCI.
| Wang, Xi; Sansam, Courtney G; Thom, Christopher S et al. (2009) Oncogenesis caused by loss of the SNF5 tumor suppressor is dependent on activity of BRG1, the ATPase of the SWI/SNF chromatin remodeling complex. Cancer Res 69:8094-101 |
