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

Oncogene volume 32, pages 4436–4447 (2013)Cite this article

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Abstract

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.

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Acknowledgements

This study is supported by grants from the National Science Council of Taiwan (NSC 99-2320-B-037-017-MY3), the Excellence for Cancer Research Center Grant, the Department of Health, Executive Yuan, Taipei, Taiwan (DOH101-TD-C-111-002), the Kaohsiung Medical University Hospital (KMUH 99–9I04) and the Kaohsiung Medical University Research Foundation (KMUER008).

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Authors and Affiliations

  1. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    Y-L Hsu & E-M Tsai

  2. Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    M-F Hou, P-L Kuo & Y-F Huang

  3. Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

    M-F Hou, P-L Kuo & Y-F Huang

  4. Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

    P-L Kuo

  5. Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

    E-M Tsai

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  1. Y-L Hsu
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Correspondence to Y-L Hsu.

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Hsu, YL., Hou, MF., Kuo, PL. et al. Breast tumor-associated osteoblast-derived CXCL5 increases cancer progression by ERK/MSK1/Elk-1/Snail signaling pathway. Oncogene 32, 4436–4447 (2013). https://doi.org/10.1038/onc.2012.444

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