GBP5 Repression Suppresses the Metastatic Potential and PD-L1 Expression in Triple-Negative Breast Cancer.

Min-Hsuan Lin,Po-Chih Chen,Shun-Wen Cheng,Hui-Wen Chiu,Yuan-Feng Lin,Tzong-Rong Ger

doi:10.3390/biomedicines9040371

Abstract

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype because of its high metastatic potential. Immune evasion due to aberrant expression of programmed cell death ligand 1 (PD-L1) has also been reported recently in metastatic TNBC. However, the mechanism underlying metastatic progression and PD-L1 upregulation in TNBC is still largely unknown. Here, we found that guanylate binding protein 5 (GBP5) is expressed in higher levels in TNBC tissues than in non-TNBC and normal mammary tissues and serves as a poorer prognostic marker in breast cancer patients. Transwell cultivation indicated that GBP5 expression is causally related to cellular migration ability in the detected TNBC cell lines. Moreover, the computational simulation of the gene set enrichment analysis (GSEA) program against the GBP5 signature generated from its coexpression with other somatic genes in TNBC revealed that GBP5 upregulation may be associated with the activation of interferon gamma (IFN-γ)-responsive and NF-κB-related signaling cascades. In addition, we found that the coexpression of GBP5 with PD-L1 was significantly positive correlation in TNBC tissues. Robustly, our data showed that GBP5 knockdown in TNBC cells harboring a higher GBP5 level dramatically suppresses the number of migrated cells, the activity of IFN-γ/STAT1 and TNF-α/NF-κB signaling axes, and the expression of PD-L1. Importantly, the signature combining a higher GBP5 and PD-L1 level predicted the shortest time interval of brain metastasis in breast cancer patients. These findings not only uncover the oncogenic function of GBP5 but also provide a new strategy to combat metastatic/immunosuppressive TNBC by targeting GBP5 activity.

Highlights

This article is an open access articleTriple-negative breast cancers (TNBCs) are immunohistochemically defined as a subset of breast cancers that are negative for human epidermal growth factor receptor-2 (HER2), estrogen receptor (ER) and progesterone receptor (PR) [1] and account for 15–20% of breast cancers [2]
The upregulation of guanylate binding protein 5 (GBP5) in primary tumors compared to normal adjacent tissues derived from non-TNBC and TNBC patients was more predominant than GBP1 (Figure 1C,D)
GBP5 upregulation shows a poor disease-free survival rate in the GSE4922 breast cancer cohort, unfavorable recurrence-free survival probabilities in the GSE9195 and GSE1379 breast cancer cohorts and a shorter time period of brain metastasis in the GSE12276 breast cancer cohort (Figure 2A–D). These findings suggest that GBP5 upregulation may correlate with the malignant evolution of TNBC

Summary

Introduction

This article is an open access articleTriple-negative breast cancers (TNBCs) are immunohistochemically defined as a subset of breast cancers that are negative for human epidermal growth factor receptor-2 (HER2), estrogen receptor (ER) and progesterone receptor (PR) [1] and account for 15–20% of breast cancers [2]. TNBC is the most aggressive subtype in breast cancer with a highly metastatic capability and lack of specific targets and targeted therapeutics [3]. Biomedicines 2021, 9, 371 several biomarkers have been reported to predict brain, lung and bone metastasis of TNBC [4], distant metastasis of TNBC still severely risks the life of patients. (PD-L1), which is an immune checkpoint inhibitor that interacts with PD-1 on the cell surface of T cells to suppress immune surveillance, has been reported as a route for the distant metastasis of TNBC [5,6]. PD-L1 has been considered as an unavoidable biomarker in advanced TNBC [7].

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Conclusion