ZEB1‐regulated inflammatory phenotype in breast cancer cells

• Published in: Molecular oncology Vol. 11; no. 9; pp. 1241 - 1262
• Main Authors: Katsura, Akihiro, Tamura, Yusuke, Hokari, Satoshi, Harada, Mayumi, Morikawa, Masato, Sakurai, Tsubasa, Takahashi, Kei, Mizutani, Anna, Nishida, Jun, Yokoyama, Yuichiro, Morishita, Yasuyuki, Murakami, Takashi, Ehata, Shogo, Miyazono, Kohei, Koinuma, Daizo
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.09.2017; John Wiley and Sons Inc; Wiley
• Subjects: Analysis; Animals; Antibodies; Base Sequence; Biomarkers, Tumor - metabolism; Breast cancer; Cancer cells; Cell culture; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Chemokines; Chemokines - metabolism; Chromatin; Culture Media, Conditioned - pharmacology; Cytokines; DNA binding proteins; DNA, Neoplasm - metabolism; Enzyme-linked immunosorbent assay; Epidermal growth factor; Ethylenediaminetetraacetic acid; Experiments; Female; Fibroblasts - drug effects; Fibroblasts - metabolism; Fibroblasts - pathology; Gene expression; Gene Expression Regulation, Neoplastic; Gene regulation; Gene set enrichment analysis; Genes; Genetic aspects; Genotype & phenotype; Granulocytes; Humans; IL‐6; IL‐8; Immunoprecipitation; Inflammation; Inflammatory Breast Neoplasms - genetics; Inflammatory Breast Neoplasms - metabolism; Inflammatory Breast Neoplasms - pathology; Interleukin 6; Interleukin 8; Ligands; Medical research; Mesenchyme; Metastasis; Mice, Inbred BALB C; Mice, Nude; Myeloid Cells - drug effects; Myeloid Cells - metabolism; Paracrine Communication - drug effects; Phenotype; Phenotypes; Prognosis; Protein binding; Proteins; R&D; Research & development; Ribonucleic acid; RNA; RNA sequencing; Scientific equipment and supplies industry; Signal Transduction - drug effects; Stem cells; Suppressor cells; TGF‐β; Transcription; Transcription factors; Transforming Growth Factor beta - pharmacology; Viral antibodies; ZEB1; ZEB2; Zinc Finger E-box Binding Homeobox 2 - metabolism; Zinc Finger E-box-Binding Homeobox 1 - genetics; Zinc Finger E-box-Binding Homeobox 1 - metabolism; Zinc finger proteins; United States; Japan; TGF-β; ZEB2; ZEB1; IL-8; IL-6
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1002/1878-0261.12098

Zinc finger E‐box binding protein 1 (ZEB1) and ZEB2 induce epithelial‐mesenchymal transition (EMT) and enhance cancer progression. However, the global view of transcriptional regulation by ZEB1 and ZEB2 is yet to be elucidated. Here, we identified a ZEB1‐regulated inflammatory phenotype in breast cancer cells using chromatin immunoprecipitation sequencing and RNA sequencing, followed by gene set enrichment analysis (GSEA) of ZEB1‐bound genes. Knockdown of ZEB1 and/or ZEB2 resulted in the downregulation of genes encoding inflammatory cytokines related to poor prognosis in patients with cancer, including IL6 and IL8, therefore suggesting that ZEB1 and ZEB2 have similar functions in terms of the regulation of production of inflammatory cytokines. Antibody array and ELISA experiments confirmed that ZEB1 controlled the production of the IL‐6 and IL‐8 proteins. The secretory proteins regulated by ZEB1 enhanced breast cancer cell proliferation and tumor growth. ZEB1 expression in breast cancer cells also affected the growth of fibroblasts in cell culture, and the accumulation of myeloid‐derived suppressor cells in tumors in vivo. These findings provide insight into the role of ZEB1 in the progression of cancer, mediated by inflammatory cytokines, along with the initiation of EMT. ZEB1 and ZEB2 regulate the production of inflammatory cytokines, such as IL‐6 or IL‐8, in breast cancer cells. The secretory proteins regulated by ZEB1 enhance cancer cell proliferation in an autocrine manner. ZEB1 also regulates the proliferation of fibroblasts and the accumulation of myeloid‐derived suppressor cells (MDSCs) through the secretory proteins in a paracrine manner.