Pathological angiogenesis RNA network analysis reveals a VEGF-independent gene signature with prognostic power for HER2+ breast cancer

Cancer and many ophthalmic diseases share angiogenesis as a common element for disease progression. Using a well-accepted animal model, we performed network coexpression analysis of mRNA and regulatory RNA to investigate the molecular landscape of pathological angiogenesis in the mouse retina. We assessed the relevance of the RNA coexpression analysis by building gene signatures for breast cancer (METABRIC cohort). Most of the gene signatures were prognostic, and one was prognostic for HER2+ breast cancer, outperforming previously reported HER2+ signatures. Interestingly, it did not include VEGF as variable, and multivariate Cox analysis further highlighted ANGPT2 as a key gene, suggesting that VEGF-independent neovascularization plays an important role in breast cancer. Next, we constructed a network linking mRNAs and regulatory RNAs involved in pathological angiogenesis; this analysis revealed three novel lncRNAs that may play a role in angiogenesis and tumor development. The novel prognostic gene signature and a comprehensive RNA-based regulatory network advance the understanding of angiogenic pathways and provide clinically relevant tools for HER2+ breast cancer stratification. Author SummaryThe formation of new blood vessels by angiogenesis is central in the origin and growth of cancer. Gene signatures are lists of genes that have strong correlation with a disease and/or its development. This study presents a novel angiogenesis gene signature with strong prognostic value for HER2+ breast cancer, an aggressive subtype of this disease. We also discovered novel long noncoding RNA genes that may have important roles in angiogenesis and in tumor development. These findings enhance our understanding of angiogenic mechanisms and offer clinically relevant tools for HER2+ breast cancer diagnosis, potentially guiding more precise therapeutic interventions.