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Enhanced expression of Duffy antigen receptor for chemokines by breast cancer cells attenuates growth and metastasis potential


In addition to the role in regulating leukocyte trafficking, chemokines recently have been shown to be involved in cancer growth and metastasis. Chemokine network in tumor neovascularity may be regulated by decoy receptors. Duffy antigen receptor for chemokines (DARC) is a specific decoy receptor binding with the angiogenic CC and CXC chemokines. To investigate the effects of DARC on the tumorigenesis and the metastasis potential of human breast cancer cells, human DARC cDNA was reintroduced into the MDA-MB-231 and MDA-MB-435HM cells which have a high capability of spontaneous pulmonary metastasis. We demonstrated that DARC overexpression induced inhibition of tumorigenesis and/or metastasis through interfering with the tumor angiogenesis in vivo. This inhibition is associated with decreasing CCL2 protein levels, and MVD and MMP-9 expression in xenograft tumors. In human breast cancer samples, we also demonstrated that low expression of the DARC protein is significantly associated with estrogen receptor (ER) status, MVD, lymph node metastasis, distant metastasis and poor survival. Our results suggest for the first time that DARC is a negative regulator of growth in breast cancer, mainly by sequestration of angiogenic chemokines and subsequent inhibition of tumor neovascularity.

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This research was supported in part by the Outstanding Young Investigator Award of National Natural Science Foundation of China (30025015), National Key Project of China (2001BA703BO5), National Natural Science Foundation of China (30371580, 30572109, 30570695) and the Grant from Shanghai Science and Technology Committee (03J14019, 04ZR14027). We would like to thank Dr Joseph A Fontana who is from John D Dingell Veterans Affairs Medical Center, Detroit, Michigan 48201, USA to review our manuscript.

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Correspondence to Z-M Shao.

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Wang, J., Ou, ZL., Hou, YF. et al. Enhanced expression of Duffy antigen receptor for chemokines by breast cancer cells attenuates growth and metastasis potential. Oncogene 25, 7201–7211 (2006).

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