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Identification of Five Cytotoxicity-Related Genes Involved in the Progression of Triple-Negative Breast Cancer.

ABSTRACT: Background: Breast cancer is one of the deadly tumors in women, and its incidence continues to increase. This study aimed to identify novel therapeutic molecules using RNA sequencing (RNA-seq) data of breast cancer from our hospital. Methods: 30 pairs of human breast cancer tissue and matched normal tissue were collected and RNA sequenced in our hospital. Differentially expressed genes (DEGs) were calculated with raw data by the R package "edgeR", and functionally annotated using R package "clusterProfiler". Tumor-infiltrating immune cells (TIICs) were estimated using a website tool TIMER 2.0. Effects of key genes on therapeutic efficacy were analyzed using RNA-seq data and drug sensitivity data from two databases: the Cancer Cell Line Encyclopedia (CCLE) and the Cancer Therapeutics Response Portal (CTRP). Results: There were 2,953 DEGs between cancerous and matched normal tissue, as well as 975 DEGs between primary breast cancer and metastatic breast cancer. These genes were primarily enriched in PI3K-Akt signaling pathway, calcium signaling pathway, cAMP signaling pathway, and cell cycle. Notably, CD8⁺ T cell, M0 macrophage, M1 macrophage, regulatory T cell and follicular helper T cell were significantly elevated in cancerous tissue as compared with matched normal tissue. Eventually, we found five genes (GALNTL5, MLIP, HMCN2, LRRN4CL, and DUOX2) were markedly corelated with CD8⁺ T cell infiltration and cytotoxicity, and associated with therapeutic response. Conclusion: We found five key genes associated with tumor progression, CD8⁺ T cell and therapeutic efficacy. The findings would provide potential molecular targets for the treatment of breast cancer.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC8762060 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Taking NVP-BEZ235 (BEZ235) as an example to screen drug response-related genes (DRRGs) and explore their potential value in triple-negative breast cancer (TNBC). Through high-throughput technique, multidimensional transcriptome expression data (mRNA, miRNA and lncRNA) of BEZ235-treated and -untreated MDA-MB-468 cell lines were obtained. Combined with transcriptome data of the MDA-MB-468 cells and TCGA-TNBC tissues, differential gene expression analysis and WGCNA were performed to identify DRRGs associated with tumor trait by simulating the drug response microenvironment (DRM) of BEZ235-treated patients. Based on DRRGs, we constructed a ceRNA network and verified the expression levels of three key molecules by RT-qPCR, which not only demonstrated the successful construction of a BEZ235-treated cell line model but also explained the antitumor mechanism of BEZ235. Four molecular subtypes related to the DRM with survival difference were proposed using cluster analysis, namely glycolysis subtype, proliferation depression subtype, immune-suppressed subtype, and immune-activated subtype. A novel prognostic signature consisting of four DRRGs was established by Lasso-Cox analysis, which exhibited outstanding performance in predicting overall survival compared with several excellent reported signatures. The high- and low-risk groups were characterized by enrichment of metabolism-related pathways and immune-related pathways, respectively. Of note, the low-risk group had a better response to immune checkpoint blockade. Besides, pRRophetic analysis found that patients in the low-risk group were more sensitive to methotrexate and cisplation, whereas more resistant to BEZ235, docetaxel and paclitaxel. In conclusion, the DRRGs exemplified by BEZ235 are potential biomarkers for TNBC molecular typing, prognosis prediction and targeted therapy. The novel DRRGs-guided strategy for predicting the subtype, survival and therapy efficacy, might be also applied to more cancers and drugs other than TNBC and BEZ235.

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Identification of Five Cytotoxicity-Related Genes Involved in the Progression of Triple-Negative Breast Cancer.

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