ABSTRACT
BACKGROUND: Cancer-associated fibroblasts (CAFs) are the most important components of the tumor microenvironment (TME). CAFs are heterogeneous and involved in tumor tumorigenesis and drug resistance, contributing to TME remodeling and predicting clinical outcomes as prognostic factors. However, the effect of CAFs the TME and the prognosis of patients with breast cancer (BC) is not fully understood. This study investigated the correlation between CAFs-activating biomarkers immune cell infiltration and survival in patients with breast cancer. METHODS: RNA sequencing data and survival information for patients with breast cancer were downloaded from The Cancer Genome Atlas (TCGA) using R software. We then analyzed the correlation between CAFs-expressing biomarkers and immune cells using the clusterProfiler package, and evaluated the prognostic role of appealing genes using the Survminer package. Immunohistochemical (IHC) staining was used to determine the expression levels of TNC in 160 breast cancer samples pathologically diagnosed as invasive ductal carcinoma that were not otherwise specified (IDC-NOS). RESULTS: Data analysis showed that CAFs-expressing genes was higher than in normal tissues (p < 0.05). Pathway enrichment revealed that the overexpression of CAFs-related genes was mainly enriched in the focal adhesion and phosphoinositol-3 kinase-serine/threonine kinase (PI3K-AKT) signaling pathways. Immune infiltration analysis suggested that high expression of CAFs-related genes was significantly positively correlated with the infiltration of naive B cells and resting dendritic cells and inversely correlated with macrophages cell infiltration. In addition, high TNC expression in tumor cells was associated with the most adverse clinicopathological features and reduced metastasis-free survival (MFS) (hazard ratio (HR) 0.574, 95% confidence interval (CI) 0.404-0.815, p = 0.035). CONCLUSIONS: This study found that CAFs may participate in immunosuppression and regulate tumor cell proliferation and invasion. High TNC expression is associated with several adverse clinicopathological features, and high TNC expression in tumor cells has been identified as an independent prognostic factor for IDC-NOS.
Fibroblasts in breast cancer are activated and usually upregulated CAFs-related genes, including tenascin C (TNC) which participate in immunosuppression through the focal adhesion and PI3K-AKT signaling pathways.TNC expression in the CAFs and tumor cells, and was associated with most adverse clinicopathological features of breast cancer.High TNC expression in CAFs or tumor cells resulted in significantly worse MFS, and as an independent prognostic factor.
