Tumor necrosis associates with aggressive breast cancer features, increased hypoxia signaling and reduced patient survival

Abstract

Abstract In the growing tumor, hypoxia may lead to tumor necrosis which is associated with more aggressive tumor features and reduced patient survival. However, there are shortcomings in our understanding of biological features and clinical significance linked to tumor necrosis. We therefore analyzed transcriptome mRNA expression profiles from primary breast tumors from TCGA and METABRIC (n = 2289) including TCGA mutational data (n = 409). We employed bioinformatics analysis and independent literature-based signatures for validation to identify alterations unique to necrosis. Necrosis was associated with aggressive tumor features and strongly predicted the basal-like breast cancer phenotype. Increased tumor cell proliferation, hypoxia, stemness, and epithelial-to-mesenchymal transition (EMT) were observed in tumors with necrosis. From gene expression data, we constructed a novel Breast Cancer Necrosis Signature (BCNS) score that was a strong predictor of the basal-like phenotype but also conveyed information relevant to the luminal subtypes of breast cancer, including prognosis. Mutational profiling pointed to enrichment of TP53 and PIK3CA mutations in tumors with and without necrosis, respectively. This study confirms the association of breast cancer necrosis with aggressive tumor features and reduced survival, and points to the BCNS score as a potential biomarker that should be further explored and validated to improve breast cancer diagnosis and management.