IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland

Abstract

High serum levels of IL-6 correlate with poor outcome in breast cancer patients. However, no data are available on the relationship between IL-6 and mammary stem/progenitor cells, which may fuel the genesis of breast cancer in vivo. Herein, we address this issue in the MCF-7 breast cancer cell line and in primary human mammospheres (MS), multicellular structures enriched in stem/progenitor cells of the mammary gland. MS from node invasive breast carcinoma tissues expressed IL-6 mRNA at higher levels than did MS from matched nonneoplastic mammary glands. In addition, IL-6 mRNA was detected only in basal-like breast carcinoma tissues, an aggressive breast carcinoma variant showing stem cell features. IL-6 treatment triggered Notch-3-dependent upregulation of the Notch ligand Jagged-1 and promotion of MS and MCF-7-derived spheroid growth. Moreover, IL-6 induced Notch-3-dependent upregulation of the carbonic anhydrase IX gene and promoted a hypoxia-resistant/invasive phenotype in MCF-7 cells and MS. Finally, autocrine IL-6 signaling relied upon Notch-3 activity to sustain the aggressive features of MCF-7-derived hypoxia-selected cells. In conclusion, these data support the hypothesis that IL-6 induces malignant features in Notch-3-expressing stem/progenitor cells from human ductal breast carcinoma and normal mammary gland.

ZEB1‐regulated inflammatory phenotype in breast cancer cells

“…IL‐8 is also associated with cancer stem cell‐like properties, and its expression correlates with poor prognosis in human pancreatic cancer (Chen et al ., 2014). Of these inflammatory cytokines, IL‐6 is reported to play especially important roles in the development of lung and breast cancers (Gao et al ., 2007; Sansone et al ., 2007). With regard to the effect of these cytokines on the EMT, previous reports focused mainly on the regulation of EMT‐related downstream factors, with ZEB1 reported as a target gene of certain inflammatory cytokines (Liu et al ., 2015; Peinado et al ., 2007).…”

“…The ZEB1‐regulated inflammatory phenotype identified in this study was characterized by enhanced breast cancer cell growth, fibroblast proliferation, and PMN‐MDSC accumulation, although each of these was observed only in certain cell types and was context dependent. The correlation between IL‐6 production and cancer proliferation has been reported in various types of cancers, including lung, prostate, and breast cancers (Gao et al ., 2007; Giri et al ., 2001; Sansone et al ., 2007; Yamaji et al ., 2004). IL‐6 secreted by cancer cells activates STAT3, and induces downstream events, including cancer cell proliferation and apoptosis inhibition.…”

NF-κB and STAT3 signaling pathways collaboratively link inflammation to cancer

“…Second, as two important transcriptional factors, NF-κB and STAT3 cooperatively bind at a subset of gene promoters to collaboratively induce their target genes expression (Yang et al, 2007). Third, many cytokines like IL-6 induced by NF-κB or STAT3 can feedback to induce STAT3 and NF-κB activation (Gao et al, 2007;Sansone et al, 2007;Grivennikov and Karin, 2008). Through their functional interaction, NF-κB and STAT3 collaboratively promote tumor development via induction of pro-tumorigenic genes including genes in angiogenesis and hypoxia, chemokines and immunosuppressive cytokines (Bollrath and Greten, 2009;Atkinson et al, 2010;He and Karin, 2011).…”

z-Leucinyl-Leucinyl-Norleucinal Induces Apoptosis of Human Glioblastoma Tumor–Initiating Cells by Proteasome Inhibition and Mitotic Arrest Response

“…To assess the effects of LLNle and DAPT on the NOTCH pathway in GBM TICs, we examined the expression of NICD transcriptional target genes JAG1, HES1, HEY1, and HEY2 (32)(33)(34) as evaluated by the GeneChip microarray studies. The values of mRNA expression for these genes showed that the effects of the two drugs were not homogeneous across the three patients (see Supplementary Data S5).…”