Abstract A58: Wnt signaling pathway components are associated with telomerase activity in breast cancer

Telomerase is a ribonucleoprotein complex that adds TTAGGG repeats to telomeres in a highly regulated fashion. Telomerase activity is absent in normal somatic cells, thus limiting their number of cell divisions due to telomere shortening. In contrast, the large majority of tumor cells upregulate telomerase activity, consistent with their ability to maintain stable telomere lengths and to divide indefinitely. Telomerase activity is detectable in over 90% of breast tumors, and it is well established that telomerase overexpression is an important step in the progression of normal epithelium to invasive breast cancer. In addition to telomerase upregulation, deregulation of various signaling pathways promotes tumor progression and metastasis. To better understand in which cellular pathway telomerase and telomeres are involved, we comprehensively quantified telomerase activity and telomere length in a panel of 52 extensively characterized breast cancer cell lines and correlated these metrics with the expression profiles of the cell lines. Across the entire panel of breast cancer cell lines, expression of 530 genes was significantly correlated with telomerase activity (FDR-corrected p-val < 0.2), while expression of 585 genes was significantly correlated with telomere length. Secondary G0-term analysis revealed that telomere length was significantly associated with genes involved in Alzheimer's disease, apoptosis regulation and negative regulation of transcription. Genes significantly correlated with telomerase activity were associated with apoptosis regulation, DNA repair, nucleotide metabolism and Wnt signaling. Several Wnt target genes, including MYC, KLF5, and FGF18 were also correlated with telomerase activity. We also used the network analysis tool PARADIGM (1) to identify cellular pathways associated with telomerase activity and telomere length. Notably, Wnt signaling components were significantly correlated with telomerase activity. Given the recent evidence that the telomerase component TERT can act as a transcriptional modulator of the Wnt/beta-catenin signaling pathway (2), we are currently testing how Wnt signaling is altered due to telomerase perturbation in breast cancer cells. (1) Vaske, C. J. et al. Inference of patient-specific pathway activities from multi-dimensional cancer genomics data using PARADIGM. Bioinformatics 2010; 26:i237–245 (2) Park, J. I. et al. Telomerase modulates Wnt signaling by association with target gene chromatin. Nature 2009; 460:66–72 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr A58.