J Cancer 2020; 11(21):6365-6375. doi:10.7150/jca.46301

Research Paper

Identification of CTLA-4 associated with tumor microenvironment and competing interactions in triple negative breast cancer by co-expression network analysis

Ziqi Peng1, Peng Su1, Yuhong Yang4, Xue Yao5, Yiqi Zhang1, Feng Jin1✉, Bowen Yang2,3✉

1. Department of Breast Surgery, the First Affiliated Hospital of China Medical University, Shenyang, China.
2. Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, China.
3. Medical Record Management Center, the First Hospital of China Medical University, Shenyang, China.
4. Disease prevention and infection control Office, Liaoning Cancer hospital & Institute, Shenyang, Liaoning Province, China.
5. Department of Surgical Oncology, the First Hospital of China Medical University, Shenyang, China.

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Citation:
Peng Z, Su P, Yang Y, Yao X, Zhang Y, Jin F, Yang B. Identification of CTLA-4 associated with tumor microenvironment and competing interactions in triple negative breast cancer by co-expression network analysis. J Cancer 2020; 11(21):6365-6375. doi:10.7150/jca.46301. Available from http://www.jcancer.org/v11p6365.htm

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Abstract

Background: The study of CTLA-4 inhibitors has been one of the hot spots in the field of tumor immunotherapy. As the most immunogenic subtype of breast cancer, Triple negative breast cancer (TNBC) has a great potential in the treatment strategy. The aim of this study was to explore the relevant genes and pathways of CTLA-4 in TNBC and to explore the prognostic value, so as to provide a theoretical basis for clinical studies.

Materials and methods: We used the data from The Cancer Genome Atlas (TCGA) to analyze the expression of CTLA-4 in different types of breast cancer, and analyzed the TNBC data of CTLA-4 related co-expression genes by WGCNA and enrichment analysis. LncRNA-miRNA-CTLA-4 network was constructed to explore the immune infiltration and immune checkpoint associated with CTLA-4. The effect of CTLA-4 on clinical outcomes in TNBC patients was also evaluated. Finally, we used data from GEO database to verify the differences of CTLA-4 in different molecular types of breast cancer and related prognostic results.

Results: CTLA-4 was significantly higher in TNBC than in Luminal subtype and Her-2 + subtype (P=0.019 and P<0.001, separately), and was significantly higher in ER and PR negative samples than in ER and PR positive samples (P<0.001). CTLA-4 related genes mainly enriched in biological process of leukocyte differentiation, regulation of leukocyte activation and T cell activation. Hsa-mir-92a was found to be a survival significance marker associated with CTLA-4 and lncRNA-miRNA-CTLA-4 network was constructed. The results of immune infiltration analysis showed that CTLA-4 was mainly related with T cell (r=0.74). For immune checkpoints analysis, CTLA-4 was mainly related to PDCD1(r=0.72) and CD28(r=0.64). In TNBC, high expression of CTLA-4 is related to good survival (P=0.0061). Results consistent with previous analysis were obtained in the GEO database, the expression of CTLA-4 in TNBC was significantly higher than that in non-TNBC (p<0.001), CTLA-4 was associated with favorable survival of TNBC (p<0.001).

Conclusion: Among all types of breast cancer, the expression of CTLA-4 was the highest in TNBC.CTLA-4 in TNBC can be regulated by hsa-mir-92a to form ceRNA networks and influence the prognosis of TNBC patients through the leukocyte differentiation, regulation of leukocyte activation and T cell activation pathway.

Keywords: CTLA-4, Immune, TNBC, hsa-mir-92a, WGCNA