The Role Of CCL5 In Poor Prognosis Of Triple Negative Breast Cancer Caused By Depression

BackgroundDepression has a high incidence in breast cancer,and plays a promoting role in the occurrence,development and metastasis of breast cancer.Among all subtypes,patients with triple negative breast cancer had the highest levels of depression,and triple negative breast cancer is the most aggressive type of breast cancer,presenting with a high recurrence rate.Tumor microenvironment plays a key role in promoting disease progression in triple negative breast cancer.Depression can cause systemic inflammation and affect the tumor microenvironment.To date,less attention has been paid to how tumor-stroma-inflammation networks formed between triple-negative breast cancer cells,stromal cells,and their close inflammatory tumor microenvironment interact and influence the course of disease in the context of depression-induced inflammation.ObjectiveTo determine whether there is an increased expression of inflammatory factors in depressed patients,to explore the effect of inflammatory factors on triple negative breast cancer cells and tumor-associated fibroblasts,a key cell in the tumor microenvironment,and finally to explore the key mechanism affecting tumor-stromainflammation networks in triple negative breast cancer patients.To find the key signal of targets,and offer a new treatment for patients with TNBC.Methods1.The Datasets were downloaded from GEO DataSets(http://www.ncbi.nlm.nih.gov/gds/).Datasets selected in this study include:depression patient datasets:GSE147582,GSE147583,GSE147584;triple negative breast cancer datasets:GSE169017,tumor-associated fibroblasts datasets:GSE161762.R language program package Bioconductor was used to analyze datasets and identify the differential genes.2.Functional enrichment and pathway enrichment:Gene Ontology(GO)enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)analysis were used for differentially expressed genes.3.Protein interaction network analysis:STRING:Functional Protein Association Networks was used to construct the protein interaction network of differentially expressed genes.4.The use of UALCAN(http://ualcan.path.uab.edu/index.html),cBioPortal(http://www.cbioportal.org/),the TIMER database(http://cistrome.dfci.h arvard.edu/TIMER/)were to analyze the expression and immune invasion of cytokines in breast cancer tissues.Results1.The expression of inflammatory genes related to monocyte in peripheral blood of depression patients was significantly up-regulated,among which TNF-α and IL-1βwas recognized as a proinflammatory factor and was highly expressed in depression patients.2.Continuous TNF-α and IL-1β stimulation,inflammatory tumor-associated fibroblasts release high levels of pro-inflammatory mediators and secrete inflammatory chemokines,which also lead to up-regulation of mitochondrial transcription-related glycolytic genes,inhibit glutamate decomposition,and provide high and more available energy for tumor cells.3.Continuous TNF-α and IL-1β stimulation of triple negative breast cancer cells predisposed the cells to a pro-inflammatory phenotype and secreted cytokines mainly contributing to the remodeling of tumor microenvironment.Meanwhile,continuous TNF-α and IL-1β stimulation reduced the down-regulation of mitochondrial transcription-related glycolytic genes in triple negative breast cancer cells,but upregulated the transcription level of OXPHOS,and increased OXPHOS level could provide higher and more available energy for tumor cells.4.CCL5 and its receptor are highly expressed in breast cancer tissues,especially triple negative breast cancer tissues,and are significantly correlated with the level of immune cell infiltration.Meanwhile,there is a significant correlation between CCL5 and the rate-limiting enzymes in glycolysis(LDHB and HK3).CCL5 and its receptors may be key participants in mediating the tumor-stromal inflammatory network in triplenegative breast cancer.It is associated with poor prognosis in triple negative breast cancer.ConclusionIn patients with breast cancer,depression as an independent risk factor can increase inflammatory factors in patients,especially TNF-α and IL-1β.Chronic stimulation of TNF-α and IL-1β leads to a pro-inflammatory phenotype of tumor-associated fibroblasts and tumor cells in the tumor microenvironment and promotes metabolic reprogramming of cells.Triple negative breast cancer,stromal cells and inflammatory factors communicate with each other in a tumor-stromal inflammatory network,in which CCL5 and its receptor act as a bridge.CCL5 and its receptor are associated with poor prognosis in triple negative breast cancer.