Potential tumorigenic programs associated with TP53 mutation status reveal role of VEGF pathway

BACKGROUND: Targeting differentially activated or perturbed tumour pathways is the key idea in individualised cancer therapy, which is emerging as an important option in treating cancers with poor prognostic profiles. TP53 mutation status is known as a core determinant of survival in breast cancer. The pathways disrupted in association with TP53 mutation status in tumours are not well characterised. METHOD: In this study, we stratify breast cancers based on their TP53 mutation status and identify the set of dysregulated tumorigenic pathways and corresponding candidate driver genes using breast cancer gene expression profiles. Expressions of these genes were evaluated for their effect on patient survival first in univariate models, followed by multivariate models with TP53 status as a covariate. RESULTS: The most strongly differentially enriched pathways between breast cancers stratified by TP53 mutation status include in addition to TP53 signalling, several known cancer pathways involved in renal, prostate, pancreatic, colorectal, lung and other cancers, and signalling pathways such as calcium signalling, MAPK, ERBB and vascular endothelial growth factor (VEGF) signalling pathways. We found that mutant TP53 in conjunction with active estrogen receptor (ER) signalling significantly influence survival. We also found that upregulation of VEGFA mRNA levels in association with active ER signalling is a significant marker for poor survival, even in the presence of wild-type TP53. CONCLUSION: Mutation status of TP53 in breast cancer involves wide ranging derangement of several pathways. Among the candidate genes of the significantly deranged pathways, we identified VEGFA expression as an important marker of survival even when controlled by TP53 mutation status. Interestingly, independent of the TP53 mutation status, the survival effect of VEGFA was found significant in patients with active ER signalling (ER/PgR+), but not in those with ER/PgR- status. Therefore, we propose more studies to focus on the role of complex interplay between TP53, ER and VEGF signalling from therapeutic and prognostic context in breast cancer. British Journal of Cancer (2012) 107, 1722-1728. doi:10.1038/bjc.2012.461 www.bjcancer.com Published online 18 October 2012 (C) 2012 Cancer Research UK