Screening of immunosuppressive factors for biomarkers of breast cancer malignancy phenotypes and subtype-specific targeted therapy

Ping Wang; Jiaxuan Liu; Yunlei Song; Qiang Liu; Chao Wang; Caiyun Qian; Shuhua Zhang; Weifeng Zhu; Xiaohong Yang; Fusheng Wan; Zhuoqi Liu; Daya Luo

doi:10.7717/peerj.7197

Screening of immunosuppressive factors for biomarkers of breast cancer malignancy phenotypes and subtype-specific targeted therapy

PeerJ. 2019 Jun 27:7:e7197. doi: 10.7717/peerj.7197. eCollection 2019.

Authors

Ping Wang^#¹, Jiaxuan Liu^#¹, Yunlei Song², Qiang Liu³, Chao Wang⁴, Caiyun Qian⁵, Shuhua Zhang⁶, Weifeng Zhu⁵, Xiaohong Yang⁵, Fusheng Wan⁵, Zhuoqi Liu⁵, Daya Luo^{5

7}

Affiliations

¹ Queen Mary School, Nanchang University, Nanchang, China.
² Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases of Ministry of Education, Gannan Medical University, Ganzhou, China.
³ National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
⁴ School of Basic Medical Sciences, Nanchang University, Nanchang, China.
⁵ Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanchang University, Nanchang, China.
⁶ Jiangxi Cardiovascular Research Institute, Jiangxi Provincial People's Hospital, Nanchang, China.
⁷ Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology, Nanchang University, Nanchang, China.

^# Contributed equally.

Abstract

We aimed to screen and validate immunosuppressive factors in luminal- and basal-like breast cancer cell lines and tissue samples associated with malignant phenotypes. The mRNA microarray datasets, GSE40057 and GSE1561, were downloaded and remodeled, and differentially expressed genes were identified. Weighted gene co-expression network analysis (WGCNA) and gene ontology (GO) and KEGG pathway enrichment analysis were performed to explore the immune-related events related to the basal-like breast cancer. The online resources, GOBO, Kaplan-Meier Plotter and UALCAN, were employed to screen for immunosuppressive factors associated with breast cancer malignant phenotypes. Immunohistochemistry was used to evaluate VEGFA and MIF levels in breast tumors and normal breast tissues; qPCRs and western blots were used to validate the expression of clinical immuno-oncology (IO) therapeutic targets CD274 (PD-L1) and IL8 in cell lines. The results showed that various immune-related events contribute to basal-like breast cancer. First, TGFβ1 and IL8 had higher average expression levels in more malignant cell lines; second, MIF and VEGFA had higher average expression levels in more malignant breast cancer tissues, and the high expression levels were associated with poor survival rate. Third, IO targets CD274 and IL8 which were confirmed to be more suitable for the treatment of basal-like breast cancer. In view of the above, during the formation and development of breast cancer, immune-related genes are always activated, and immunosuppressive factors, IL8, TGFβ1, MIF, and VEGFA are up-regulated. Such molecules could be used as biomarkers for breast cancer prognosis. However, because individual immune-related factors can play several biological roles, the mechanistic relationship between immunosuppressive factors and breast cancer malignant phenotypes and the feasibility of their application as drug targets require further investigation.

Keywords: Biomarker; Breast cancer; Immunosuppressive factor; Online databases; Therapeutic target.

Grants and funding

This work was supported by National Natural Science Foundation of China (No. 81160248, 81360313, 81560464) (to Daya Luo and Zhuoqi Liu), Natural Science Foundation of Jiangxi Province (No. 20151BAB205058, 20171BAB205055) (to Daya Luo and Zhuoqi Liu), Innovation Foundation for Graduate Students of Nanchang University (No. CX2015181) (to Yunlei Song). There was no additional external funding received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.