Identification of Breast Cancer Subtypes Based on Gene Expression Profiles in Breast Cancer Stroma

Background: Tumor stroma is a heterogeneous cellular component in the tumor microenvironment of breast cancer. However, very few studies have explored the identification of breast cancer subtypes based on highly heterogeneous tumor stromal signatures. Materials and Methods: Using a combined dataset composed of 8 gene expression profil-ing datasets for breast tumor stroma, we clustered breast cancers based on the expression levels of 100 genes whose expression values were most variable across all samples. Furthermore, we investigated the molecular features of the breast cancer subtypes identified. Results: We identified 2 breast cancer subtypes, termed SBCS-1 and SBCS-2. We found that the contents of stroma and immune cells were lower in SBCS-1 than in SBCS-2, while the proportion of tumor cells was higher in SBCS-1. SBCS-1 was enriched in cancer-associated pathways, including ribosomes, cell cycle, RNA degradation, RNA polymerase, DNA replication, oxidative phosphorylation, proteasome, spliceosome, and glycolysis/gluconeogenesis. SBCS-2 was enriched in pathways of graft versus host disease, type 1 diabetes melli-tus, intestinal immune network for IgA production, allograft rejection, and steroid hormone biosynthesis. Moreover, many oncogenic biological processes were highly activated in SBCS-1, including proliferation, stemness, epithelial-to-mesenchymal transition (EMT), and angiogenesis. Gene co-expression network analysis identified prognostic hub genes, transcription factor encoding genes (PFDN5 and EZH2), and protein kinase encoding gene (AURKA) in a gene module highly enriched in SBCS-1. Conclusion: Based on the gene expression profiles in breast cancer stroma, breast cancer can be divided into 2 subtypes, which have significantly different molecular, and clinical characteristics. The identification of new subtypes of breast cancer has clinical implications for the management of this disease.