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The chemokine receptor CCR4 promotes tumor growth and lung metastasis in breast cancer

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Abstract

Increasing evidence has shown that chemokines and chemokine receptors are associated with tumor growth and metastasis. CCR4, an important chemokine receptor for regulating immune homeostasis, is thought to be involved in hematologic malignancies and has also recently implicated in some solid tumors, such as gastric cancer. The possible role of CCR4 in breast cancer has not been well elucidated. In this study, we show that CCR4 is differentially expressed in human breast cancer cell lines. Specifically, we find that CCR4 is overexpressed in breast cancer cell lines with high metastatic potential. More importantly, we used a combination of overexpression and RNA interference to demonstrate that CCR4 promotes breast tumor growth and lung metastasis in mice. Furthermore, we find that microvessel density is significantly increased in tumors formed by CCR4-overexpressing cells and decreased in those formed by CCR4-knockdown cells. We find that overexpression of CCR4 can enhance the chemotactic response of breast cancer cells to CCL17. However, the expression of CCR4 does not affect the proliferation of breast cancer cells in vitro. Furthermore, we show that CCR4 expression is positively correlated with HER2 expression, tumor recurrence and lymph node, lung and bone metastasis (P < 0.05). Multivariate analysis showed that CCR4 expression is a significant independent prognostic factor for overall survival (P = 0.036) but not for disease-free survival in patients with breast cancer (P = 0.071). Survival analysis indicated a strong association between CCR4 expression and lower overall survival (P = 0.0001) and disease-free survival (P = 0.016) in breast cancer.

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Acknowledgments

We thank the studied women for willingness to cooperate with our study. We thank prof. Ying Wang (Center for Human Disease Genomics, Peking University, Peking, China) for kindly providing the coding sequence of CCR4. This research is supported by the Shanghai United Developing Technology Project of Municipal Hospitals (SHDC12010116), Key Clinical Program of the Ministry of Health (2010-2012), and the National Natural Science Foundation of China (30971143, 30972936, 81001169).

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No potential conflicts of interest were disclosed.

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Authors and Affiliations

  1. Breast Cancer Institute, Cancer Hospital, Department of Oncology, Shanghai Medical College, Institutes of Biomedical Science, Fudan University, Shanghai, 200032, China

    Ji-Yu Li, Zhou-Luo Ou, San-Jian Yu, Xiao-Li Gu, Chen Yang, Ao-Xiang Chen, Gen-Hong Di, Zhen-Zhou Shen & Zhi-Ming Shao

  2. Department of Breast Surgery, Cancer Hospital/Cancer Institute, Breast Cancer Institute, Fudan University, 399 Ling-Ling Road, Shanghai, 200032, China

    Zhi-Ming Shao

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  1. Ji-Yu Li
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Correspondence to Zhi-Ming Shao.

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Ji-Yu Li and Zhou-Luo Ou contributed equally to this work.

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Li, JY., Ou, ZL., Yu, SJ. et al. The chemokine receptor CCR4 promotes tumor growth and lung metastasis in breast cancer. Breast Cancer Res Treat 131, 837–848 (2012). https://doi.org/10.1007/s10549-011-1502-6

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