Exploring angiogenic pathways in breast cancer: Clinicopathologic correlations and prognostic implications based on gene expression profiles from a large-scale genomic dataset.

Abstract

Background: Angiogenesis inhibitors targeting VEGF, or its receptors have consistently produced disappointing clinical outcomes in breast cancer. Therefore, there is an urgent need to explore alternative angiogenic pathways in breast cancer. This study aimed to describe the gene expression of pivotal pro-angiogenic genes in breast cancer and to further analyze the associations with the clinicopathologic tumor features, prognostic factors, and overall survival. Such findings would expand the understanding of the role of different angiogenic pathways in breast cancer pathogenesis and identify patients at risk of more aggressive disease who could be eligible for intense treatment regimens. Additionally, exploring angiogenic pathways helps identify new potential drug targets for breast cancer.

Methods: The mRNA expression levels for eight pro-angiogenic genes [VEGFA, HGF, FGF1, FGF2, ANGPT1, ANGPT2, PDGFA, and PDGFB] were obtained from the METABRIC (Molecular Taxonomy of Breast Cancer International Consortium) dataset available at cBioPortal public domain. Pertinent demographic and tumor information were retrieved.

Results: VEGFA and ANGPT2 genes had the highest expression levels with average mRNA log intensities of 7.18±0.7 and 7.11±0.53, respectively. VEGFA expression was not correlated with the expression of other pro-angiogenic genes, the clinicopathologic tumor features, and the overall survival of patients. FGF1, ANGPT1, and PDGFA mRNA levels were negatively correlated with the age of patients at diagnosis. The expression of FGF1 and FGF2 correlated inversely with tumor size and the Nottingham Prognostic Index (p = 0.03 and p = 0.002, respectively). Expression of HGF was significantly associated with advanced tumor stage (p<0.05). Expression of ANGPT1 and ANGPT2 was associated with hormone receptor-negative status and the non-luminal subtypes. PDGFB expression was significantly higher in patients with high-grade disease and HER2-positive status. Patients with high expression status of ANGPT2 and PDGFB had significantly reduced overall survival compared to those with low expression levels of these genes (p = 0.004 and p = 0.0001, respectively).

Conclusions: In this dataset of patients with breast cancer, the expression levels of 8 different pro-angiogenic genes revealed remarkable differences in terms of their association with clinicopathologic tumor characteristics and prognosis. The expression of ANGPTs and PDGFs was associated with adverse tumor features, worse prognosis, and reduced survival in patients. Targeting ANGPTs and PDGF pathways could provide new insights for effective anti-angiogenic drugs in breast cancer.