R. Ramanathan1, A. L. Olex2, L. J. Fernandez1, A. R. Wolen2, D. Fenstermacher2, M. Dozmorov3, K. Takabe1 1Virginia Commonwealth University Medical Center,Surgery,Richmond, VA, USA 2Virginia Commonwealth University,Center For Clinical And Translational Research,Richmond, VA, USA 3Virginia Commonwealth University,Biostatistics,Richmond, VA, USA
Introduction:
Breast cancer is the second most common cancer affecting women in the United States, constituting an estimated 232,670 new cases in 2014. Angiogenesis is one of the known hallmarks of cancer that is essential for cancer progression and aggressiveness. The angiopoietin-2 (Ang2) ligand and its Tie receptors constitute one of the upstream cascades that control the angiogenic switch. However, its impact on cancer progression and prognosis has been a topic of debate, since its effect has been ‘context dependent’, i.e. results change depending on the experimental setting used. Using The Cancer Genome Altas (TCGA), we investigate associations between breast cancer patient survival and genomic expressions of genes involved in the Ang2-Tie pathway.
Methods:
The gene expressions of Ang2, Tie1 and Tie2 in the Ang2-Tie pathway and of VEGFA and VEGF receptors in the VEGF pathway were analyzed using the RNA-seq data for 886 individual patient tumor transcriptomes from TCGA. The mean age of the cohort was 58.5 ± 13.2 years. We identified gene-specific expression thresholds to dichotomize patients into high and low expression for a survival analysis using in-house R scripts and R’s ‘survival’ package. Associations with overall and disease free survival were investigated for each gene individually and for the combined effect of multiple genes.
Results:
Individual analysis of the genes revealed decreased disease free survival among tumors with high pro-angiogenesis factor Ang2 expression (p=0.04) and decreased overall survival with high Ang2 expression (p=0.03). High co-expression of Ang2 and endothelial cell surface receptors Tie1 and Tie2 were associated with poor overall survival. In the multi-gene analysis, disease free survival was significantly decreased among patients with high co-expression of Ang2 and VEGFA, and Tie1 and VEGF receptors 1-3.
Conclusion:
Ang2 binds to Tie2 to stimulate endothelial cell sprouting and angiogenesis, and high Ang2 expression is correlated with increased tumor vascularity in animal models. Ang2 also stimulates the well-studied downstream vascular endothelial growth factor (VEGF) pathways. Our results, from a large prospectively collected national breast cancer genome database, provide clinical evidence of the deleterious effect of Ang2 and Tie receptor overexpression in breast cancer patient survival through the Ang2-Tie and VEGF pathways. Novel therapies targeting this pathway are therefore expected to improve survival.
