Role of TMS1 Silencing in the Resistance of Breast Cancer Cells to Apoptosis
Annual summary rept. 17 Jul 2003-16 Jul 2006
EMORY UNIV ATLANTA GA
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Aberrant DNA methylation of promoter region CpG islands is associated with gene silencing and serves as an alternative to mutations in the inactivation of tumor suppressor genes in human cancers. We identified a gene TMS1 for Target of Methylation-mediated Silencing that is subject to such epigenetic silencing in a significant proportion of human breast and other cancers. TMS1 encodes a bipartite intracellular signaling molecule with proposed roles in apoptosis and inflammation. However the precise role of this protein in apoptosis has not been clearly defined, and the consequence of TMS1 silencing on the pathogenesis of breast cancer is unknown. In this study we identified two novel roles for TMS1 in apoptosis activation of caspase-8 and subsequent apoptosis induced by TNFa, and apoptosis induced by detachment from the extracellular matrix. Importantly, loss of TMS1 expression severely inhibits apoptosis induced by these stimuli. Therefore, loss of TMS1 expression through epigenetic silencing may contribute to breast carcinogenesis by dampening the apoptotic response to TNFa, and allowing cells to bypass cell death induced by detachment from the extracellular matrix.
- Medicine and Medical Research