| 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 T&barbelow;arget of M&barbelow;ethylation-mediated S&barbelow;ilencing) 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 TNFalpha, 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 TNFalpha, and allowing cells to bypass cell death induced by detachment from the extracellular matrix. |
