Breast tumor-associated osteoblast-derived CXCL5 increases cancer progression by ERK/MSK1/Elk-1/Snail signaling pathway

• Published in: Oncogene Vol. 32; no. 37; pp. 4436 - 4447
• Main Authors: Hsu, Y-L, Hou, M-F, Kuo, P-L, Huang, Y-F, Tsai, E-M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.09.2013; Nature Publishing Group
• Subjects: 631/67/322/803; 631/80/86; 692/420/755; 692/699/67/1347; Acetylation; Animals; Apoptosis; Bone cancer; Bone tumors; Breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Care and treatment; Cell adhesion & migration; Cell Biology; Cell Line, Tumor; Cell Movement; Cellular signal transduction; Chemokine CXCL5 - pharmacology; Chemokines; Culture Media, Conditioned - pharmacology; Development and progression; Disease Models, Animal; Disease Progression; E-cadherin; Enzyme Activation - drug effects; Epithelial-Mesenchymal Transition - drug effects; Epithelial-Mesenchymal Transition - genetics; ets-Domain Protein Elk-1 - metabolism; Extracellular signal-regulated kinase; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; Fractures; Gene Expression Regulation, Neoplastic - drug effects; Genetic aspects; Histone H3; Histones; Histones - metabolism; Human Genetics; Humans; Internal Medicine; Kinases; MAP kinase; Medicine; Medicine & Public Health; Mesenchyme; Metastases; Metastasis; Mice; Microenvironments; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplastic processes; Observations; Oncology; original-article; Osteoblasts; Osteoblasts - metabolism; Pathology; Phosphorylation; Protein Binding; Raf protein; Ribosomal Protein S6 Kinases, 90-kDa - metabolism; Signal transduction; Signal Transduction - drug effects; Skeleton; Snail Family Transcription Factors; Therapeutic targets; Transcription Factors - genetics; Transcription Factors - metabolism; Tumors; United Kingdom; breast cancer; osteoblasts; cancer progression; CXCL5
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2012.444

The skeleton is the most common metastatic site for breast cancer, with bone metastasis causing pain as well as risk of pathological fractures. Interaction between tumors and the bone microenvironment creates a vicious cycle that accelerates both bone destruction and cancer progression. This study is the first to analyze the soluble factors secreted by breast tumor-associated osteoblasts (TAOBs), which are responsible for promoting cancer progression. The addition of CXCL5 (chemokine (C-X-C motif) ligand 5), present in large amounts in TAOB-condition medium (TAOB-CM), mimicked the inductive effect of TAOB-CM on breast cancer epithelial–mesenchymal transition, migration and invasion. In contrast, inhibition of CXCL5 in OBs decreased TAOB-mediated cancer progression. Inducement of MCF-7 and MDA-MB-231 cancer progression by TAOB-derived CXCL5 is associated with increased Raf/MEK/ERK activation, and mitogen- and stress-activated protein kinase 1 (MSK1) and Elk-1 phosphorylation, as well as Snail upregulation. Activation of Elk-1 facilitates recruitment of phosphorylated MSK1, which in turn enhances histone H3 acetylation and phosphorylation (serine 10) of Snail promoter, resulting in Snail enhancement and E-cadherin downregulation. Moreover, mice treated with anti-CXCL5 antibodies showed decreased metastasis of 4T1 breast cancer cells. Our study suggests that inhibition of CXCL5-mediated ERK/Snail signaling is an attractive therapeutic target for treating metastases in breast cancer patients.