Identification of Breast Cancer LCK Proto-Oncogene as a Master Regulator of TNBC Neutrophil Enrichment and Polarization

Abstract

The role of neutrophils in breast cancer shows that the N1 proinflammatory subtype can suppress and attack the tumor. In contrast, the N2 pro-tumor subtype aids the tumor in its survival, progression, and metastasis. Recently, more focus has been directed to the role of innate myeloid cells, specifically neutrophils, in regulating the responses of lymphoid populations both in the progression of cancer and in response to therapy. However, the exact crosstalk between breast cancer cells and neutrophils is poorly understood. In this work, we used in-silico assays to investigate the role of the bidirectional effect of neutrophils on metastatic TNBC. Our reanalysis of publicly available data reveals that most TNBC’s classified within the CE2 subtype are leukocyte-poor and have four major cell types in their ecotypes: dendritic cells, macrophages, fibroblasts, and epithelial cells. Further immune deconvolution of these patients revealed that a few cells significantly differed between groups, including macrophages, neutrophils, and T cells. All BC showed lower infiltrating neutrophils compared to healthy surrounding tissue. Treated TNBCs improved the count of infiltrating neutrophils in TNBC. Most TNBC patients have a unique CE2 ecotype, characterized by more basal-like epithelial cells, more neutrophils, and fewer mononuclear lymphocytes (B cells, macrophages M1, T cell CD4+ (non-regulatory), and T cell CD8+ and T regs). This can be related to our finding that CE2 TNBCs are characterized by a lower LCK and higher ERBB2, and their top DEGs are related to leukocyte activation and NFKB pathway.

The therapeutic effect and targets of herba Sarcandrae on breast cancer and the construction of a prognostic signature consisting of inflammation-related genes

“…In this study, 101 DEGs associated with BRCA inflammation, including 55 upregulated genes and 46 downregulated genes, were identified by analyzing TCGA-BRCA data. Univariate analysis and bioinformatics analysis revealed that the effects of the BST2 [ 31 ], CXCL6 [ 32 ], GPR132 [ 33 ], IL12B [ 34 ], IL18 [ 35 ], IL1R1 [ 36 ], IL2RB [ 37 ], IRF1 [ 38 ], IRF7 [ 39 ], KCNMB2 [ 40 ], LCK [ 41 ], RGS1 [ 42 ], SELL, TACR1, TAPBP and TNFRSF1B [ 43 ] genes on the prognosis of patients with BRCA were significant, and a search of the literature revealed that some of the 16 genes are therapeutic targets and risk predictors for BRCA [ 44 , 45 ]. A prognostic model for the 16 inflammatory genes was constructed, and the predictive ability of this prognostic model was verified, highlighting the prognostic survival curves and plots containing 16 gene signatures and clinicopathological parameters showing great prognostic efficacy, which might allow clinicians to make judgments about outcomes for individual patients.…”