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RKIP regulates CCL5 expression to inhibit breast cancer invasion and metastasis by controlling macrophage infiltration
Author(s) -
Ila Datar,
Xiaoliang Qiu,
Hong Zhi,
Miranda Yeung,
Shweta Aras,
Ivana de la Serna,
Fahd Al-Mulla,
Jean Paul Thiery,
Robert Trumbly,
Fujun Xuan,
Hongjuan Cui,
Kam C. Yeung
Publication year - 2015
Publication title -
oncotarget
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.373
H-Index - 127
ISSN - 1949-2553
DOI - 10.18632/oncotarget.5176
Subject(s) - breast cancer , infiltration (hvac) , cancer research , metastasis , ccl5 , medicine , cancer , immunology , il 2 receptor , physics , immune system , t cell , thermodynamics
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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