RKIP regulates CCL5 expression to inhibit breast cancer invasion and metastasis by controlling macrophage infiltration
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Ila Datar1, Xiaoliang Qiu1, Hong Zhi Ma1, Miranda Yeung1, Shweta Aras1, Ivana de la Serna1, Fahd Al-Mulla2, Jean Paul Thiery3, Robert Trumbly1, Xuan Fan4, Hongjuan Cui4 and Kam C. Yeung1
1 Department of Biochemistry and Cancer Biology, University of Toledo, College of Medicine, Health Science Campus, Toledo, OH, USA
2 Kuwait University, Faculty of Medicine. P.O. Box 24923, Safat, Kuwait
3 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
4 State Key Laboratory Of Silkworm Genome Biology, Chongqing, China
Kam C. Yeung, email:
Keywords: metastasis suppressor, RKIP, tumor microenvironment, CCL5
Received: February 22, 2015 Accepted: July 16, 2015 Published: August 13, 2015
Accumulating evidence suggests that presence of macrophages in the tumor microenvironment add to the invasive and tumor-promoting hallmarks of cancer cells by secreting angiogenic and growth factors. RKIP is a known metastasis suppressor and interferes with several steps of metastasis. However, the mechanistic underpinnings of its function as a broad metastasis suppressor remain poorly understood. Here, we establish a novel pathway for RKIP regulation of metastasis inhibition through the negative regulation of RANTES/CCL5 thereby limiting tumor macrophage infiltration and inhibition of angiogenesis. Using a combination of loss- and gain-of- function approaches, we show that RKIP hinders breast cancer cell invasion by inhibiting expression of the CC chemokine CCL5 in vitro. We also show that the expression levels of RKIP and CCL5 are inversely correlated among clinical human breast cancer samples. Using a mouse allograft breast cancer transplantation model, we highlight that ectopic expression of RKIP significantly decreases tumor vasculature, macrophage infiltration and lung metastases. Mechanistically, we demonstrate that the inhibition of the CCL5 expression is the cause of the observed effects resulting from RKIP expression. Taken together, our results underscore the significance of RKIP as important negative regulator of tumor microenvironment.
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