Abstract
Interleukin-34 (IL-34) is a ligand for the CSF-1R and has also two additional receptors, PTPRZ1 and syndecan-1. IL-34 plays a role in innate immunity, inflammation, and cancer. However, the role of IL-34 in breast cancer is still ill-defined. We analyzed IL-34 mRNA expression in breast cancer cell lines and breast cancer patients and applied established computational approaches (CIBERSORT, ESTIMATE, TIMER, TCIA), to analyze gene expression data from The Cancer Genome Atlas (TCGA). Expression of IL-34 was associated with a favorable prognosis in luminal and HER2 but not basal breast cancer patients. Gene expression of CSF-1 and CSF-1R was strongly associated with myeloid cell infiltration, while we found no or only weak correlations between IL-34, PTPRZ1, syndecan-1 and myeloid cells. In vitro experiments showed that tyrosine phosphorylation of CSF-1R, ERK, and FAK and cell migration are differentially regulated by IL-34 and CSF-1 in breast cancer cell lines. Collectively, our data suggest that correlation of IL-34 gene expression with survival is dependent on the molecular breast cancer subtype. Furthermore, IL-34 is not associated with myeloid cell infiltration and directly regulates breast cancer cell migration and signaling.
Highlights
Breast cancer is the most common cancer among women worldwide and remains the leading cause of cancer death among females [1]
Summary of the distributions of the gene expression values were presented by boxplots in Figure 1A with the median, spread and outliers showing for each gene
colony-stimulating factor-1 (CSF-1), CSF-1R, and IL-34 were weakly negatively associated with tumor purity, while the lack of association between immune cell infiltration and gene expression of PTPRZ1 and syndecan-1 was reflected by tumor purity values (Figure 7, Table 4, Supplementary Table 1). These findings suggest that IL-34 and its receptors PTPRZ1 and syndecan-1 are not linked to myeloid cells, whereas the CSF-1/CSF-1R axis shows a strong correlation with myeloid cells in the tumor microenvironment
Summary
Breast cancer is the most common cancer among women worldwide and remains the leading cause of cancer death among females [1]. Its malignancy grade and patient prognosis is influenced by various mutations that occur in the tumor cell, and by the tumor microenvironment (TME) [2]. The TME of breast cancer consists of a heterogeneous collection of cells and is enriched in highly active immune cells which, together with cytokines, play an important role in the regulation of breast cancer [3, 4]. The host immune response during breast cancer is dynamic and can affect tumor growth both in promotive and suppressive ways. The prognosis of breast cancer patients is influenced by the density, composition and activity of the tumor immune infiltrate [3]. The addition of tumor-promoting inflammation as the seventh hallmark of cancer reflects the double-edged role of inflammatory processes in cancer progression [5]
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