Role of TMS1 Silencing in the Resistance of Breast Cancer Cells to Apoptosis
Abstract
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. Our lab has identified novel gene, TMS1, that is aberrantly methylated and silenced in human breast tumors. TMS1 is a bipartite signalling molecule that functions in the regulation of apoptosis and inflammation. It is our hypothesis that epigenetic silencing of TMS1 contributes to breast carcinogenesis by allowing cells to bypass normal apoptotic cues, and, as a consequence may cause cells to be more resistant to chemotherapeutic agents. The goals of this proposal are to study the role of TMS1 in breast cell apoptosis by developing breast cells stably knocked down for TMS1 expression using siRNA technology and to determine the impact of TMS1 loss on the response of breast cancer cells to anticancer agents and other apoptotic stimuli. Thus far, we have determined that overexpression of TMS1 induces a time-dependent apoptotic response characterized by cleavage of the initiator caspase-8, the downstream caspase-3, and the death substrate PARP. TMS1-induced apoptosis was blocked by inhibitors of caspase-8, suggesting a role in death receptor mediated apoptosis. The death receptor ligands TNFalpha and TRAIL upregulate TMS1 expression in breast epithelial cells. The activation of TMS1 by death receptors is mediated at the level of transcription and requires the activity of the NF-kB and JNK signalling pathways. Upregulation of TMS1 by TNFalpha and TRAIL and subsequent activation of caspase-8 could function as an amplification loop necessary to achieve cell death by the death receptors in some cell types, including breast cells. These results may also have therapeutic implications in that the methylation status of TMS1 in human tumors may influence sensitivity to TRAIL, which is currently undergoing clinical trial.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2004
- Accession Number
- ADA428931
Entities
People
- Melissa J. Parsons
- Paula M. Vertino
Organizations
- Emory University