Differential prognostic impact of interleukin-34 mRNA expression and infiltrating immune cell composition in intrinsic breast cancer subtypes

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.

Interleukin‐34 mediated by hepatitis B virus X protein via CCAAT/enhancer‐binding protein α contributes to the proliferation and migration of hepatoma cells

“…indicated that IL-34 could directly regulate the proliferation and migration of tumour cells. 26 We explored whether HBX could mediate the function of HCC cells through IL-34. Consistent with our previous studies, 18,45 HBX could promote the growth and migration of HCC cells.…”

“…18 In addition, current researches suggest that IL-34 contribute to the proliferation and migration of breast cancer cells. 26 We examined whether IL-34 promoted the proliferation and migration of HCC cells mediated by HBX. We Current studies indicate that, many cytokines, including IL-17, IL-6 and IL-37, could regulate the function of HCC cells by an autocrine manner.…”

Role of Interleukin-34 in Cancer

“…Cytotoxic therapies induce mammary epithelial cells to produce monocyte/macrophage recruitment factors, including M-CSF-1 and IL-34, which together enhance M-CSF1-R-dependent macrophage infiltration. Blockade of macrophage recruitment with M-CSF1-R-signaling antagonists improves survival of mammary-tumor-bearing mice by slowing primary tumor development, reducing pulmonary metastasis, decreasing vessel density and appearance of antitumor immune programs, fostering tumor suppression in a CD8 + T-cell-dependent manner [39] Lung and brain metastases derived from breast cancer express M-CSF-1 and IL-34 [39] The IL-34 receptor Sydecan-1 (CD138) is increased in breast cancer and associates with high-grade tumors [40] Expression of IL-34 is associated with a favorable prognosis in luminal and HER2, but not basal, breast cancer patients [41] Human ovarian cancer…”

“…For instance, IL-34 hampers proliferation, clonogenicity, and motility of glioblastoma cells and promotes the differentiation of monoblastic leukemia cells into monocyte-like cells [16,56]. Analysis of IL-34 RNA expression and breast cancer subtypes showed that high IL-34 expression correlated with a better prognosis in luminal and HER2 subtypes and worse prognosis in the basal one [41]. These findings were unexpected and surprising, as expression of both M-CSF-1 and M-CSF1-R has been linked to aggressive behavior and poor prognosis in breast cancer patients [57,58].…”

Drainage of inflammatory macromolecules from brain to periphery targets the liver for macrophage infiltration

“…The receptor tyrosine kinase CSF1R (also known as Fms) pathway regulates migration, differentiation, proliferation, and survival at varying degrees of different tissue-resident macrophages and monocytes in mammals and zebrafish [56,57]. Recent studies have implicated a role for this pathway in macrophage recruitment in disease, including the assembly of tumorassociated macrophages in various cancers [98][99][100][101][102]. Of particular interest IL-34 is elevated and implicated in the inflammation process of several inflammatory diseases including rheumatoid arthritis, inflammatory bowel disease, and Sjogren's syndrome [103][104][105][106][107].…”