Exposing the role of MYC in small cell carcinoma of the ovary hypercalcemic type

项目总结/文摘

PROJECT SUMMARY/ABSTRACT SCCOHT is rare and often fatal ovarian cancer, with the average age of diagnosis being around 24 years old. The molecular pathogenesis of SCCOHT is overwhelmingly linked to mutations in the SMARCA4 gene, which encodes the BRG1 subunit of the SWI/SNF chromatin remodeling complex. Numerous studies have shown that loss of BRG1 impacts normal SWI/SNF function in several ways, which together most likely conspire to drive the SCCOHT phenotype. SCCOHT cancers fall into a group of about 20% of all cancers that have loss-of-function SWI/SNF subunit mutations. Across these cancers mechanisms are emerging that can explain the maintenance of the cancer state following loss of particular SWI/SNF subunits. One common finding is that in many SWI/SNF-altered cancers “residual” SWI/SNF complexes are retained that function to promote a pro-tumorigenic gene expression program. A second and more new finding that is emerging is that some underlying mechanisms of tumorigenesis may involve interactions between SWI/SNF and oncoprotein transcription factors, such as MYC. Recently, activation of oncogenic MYC target gene expression was reported in SCCOHT, a phenomenon that may be due to interactions between MYC and SWI/SNF subunits. This project is built on the hypothesis that loss of critical SWI/SNF subunits can 1) allow residual SWI/SNF complexes to alter gene expression patterns that overall promote cancer processes and 2) activate the functionality of MYC and may do so through changes in MYC-SWI/SNF interactions. Support for this hypothesis comes from published data showing that in multiple SWI/SNF-altered cancer cell lines, including SCCOHT, core residual SWI/SNF subunits are bound to chromatin at essential MYC target genes. In addition, blocking residual SWI/SNF complex function in certain SWI/SNF-altered cancer cells decreases expression of genes bound by MYC, suggesting that residual SWI/SNF complexes can facilitate MYC-target gene expression. Together these data provide the rationale for examining the role of residual SWI/SNF subunits and MYC in supporting oncogenic gene expression programs in SCCOHT, and point to the possibility there there are broad, significant mechanisms at work across various SWI/SNF-altered cancers. Specific Aim 1 will use genomic and genetic approaches to assess what residual SWI/SNF subunits are doing in SCCOHT cells and how they influence pro-tumorigenic gene expression. Specific Aim 2 will define the action of MYC in SCCOHT cells and expose the impact that both residual SWI/SNF subunits and BRG1 reintroduction has on MYC activities. At the completion of these studies we will know the gene networks regulated by MYC and residual SWI/SNF subunits in SCCOHT cells and directly challenged the significance of each in driving multiple facets of SCCOHT function.