Abstract #5139: The inflammatory cytokine TNF-\#945; induces rapid, reversible telomere shortening in breast cancer cell lines

Background: Telomeres are the protein-nucleic acid structures that stabilizechromosome ends. This prevents genomic instability that results from chromosome fusion, amplification, loss, and structural rearrangement. The lengths of telomeres are determined by two competing processes. The first process is proliferation dependent telomere loss. The second process is telomere elongation, which is catalyzed by telomerase, the specialized reverse transcriptase that adds telomere DNA to chromosome ends. These competing processes of telomere length maintenance are most likely responsible for the variation in telomere length observed in most normal tissues. However, telomeres in breast tumor tissues are drastically mis-regulated. Furthermore, telomere length in tumor tissues is not correlated with the known mechanisms of telomere regulation, suggesting additional processes that affect telomere dynamics in tumor tissues It has been documented that telomere attrition is associated with diseases of chronic inflammation. There is also substantial evidence that inflammatory processes play a direct role in the initiation, progression and metastasis of several cancers. Based on these observations, it is likely that inflammatory cytokines in the breast cause telomere attrition, resulting in genomic instability, tumor initiation and progression. The pro-inflammatory cytokine, tumor necrosis factor alpha (TNF-\#945;), has been implicated in both chronic inflammation and cancer development and progression, and is a likely candidate for telomere regulation. Hypothesis: TNF-\#945; will accelerate telomere loss and cell death through mechanisms other than proliferation dependent telomere loss or telomerase dependent telomere gain. Objective: The purpose of this research was to determine whether TNF-\#945; induces a proliferation-independent and telomerase-independent mechanism of telomere attrition. Methods: Breast cancer cell lines, MCF7, MDA MB231 and MCF 10A were treated with 10 ng/ml of TNF-\#945; for 28 days to mimic inflammation in a breast tumor. Telomere length, telomerase activity, genomic instability and proliferation rates were evaluated. Results: We have demonstrated that TNF-\#945; induces telomere shortening in breast cell lines. Treatment of MCF-7 cells with TNF-\#945; causes telomere attrition throughout the 28 day treatment period to 50% of control values. Removal of TNF-\#945; resulted in rapid recovery of telomeres to their original length. Treatment of MDA-MB231 cells with TNF-\#945; resulted in rapid shortening of telomeres until the 14^th day of treatment. After this time period, telomere length recovered even in the presence of TNF- \#945;.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5139.