title: RKIP regulates CCL5 expression to inhibit breast cancer invasion and metastasis by controlling macrophage infiltration.
abstract: 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.
authors.affiliation: Department of Biochemistry and Cancer Biology, University of Toledo, College of Medicine, Health Science Campus, Toledo, OH, USA.
authors.forename: Ila
authors.initials: I
authors.lastname: Datar
authors.affiliation: Department of Biochemistry and Cancer Biology, University of Toledo, College of Medicine, Health Science Campus, Toledo, OH, USA.
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Qiu
authors.affiliation: Department of Biochemistry and Cancer Biology, University of Toledo, College of Medicine, Health Science Campus, Toledo, OH, USA.
authors.forename: Hong Zhi
authors.initials: HZ
authors.lastname: Ma
authors.affiliation: Department of Biochemistry and Cancer Biology, University of Toledo, College of Medicine, Health Science Campus, Toledo, OH, USA.
authors.forename: Miranda
authors.initials: M
authors.lastname: Yeung
authors.affiliation: Department of Biochemistry and Cancer Biology, University of Toledo, College of Medicine, Health Science Campus, Toledo, OH, USA.
authors.forename: Shweta
authors.initials: S
authors.lastname: Aras
authors.affiliation: Department of Biochemistry and Cancer Biology, University of Toledo, College of Medicine, Health Science Campus, Toledo, OH, USA.
authors.forename: Ivana
authors.initials: I
authors.lastname: de la Serna
authors.affiliation: Kuwait University, Faculty of Medicine, Safat, Kuwait.
authors.forename: Fahd
authors.initials: F
authors.lastname: Al-Mulla
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Jean Paul
authors.initials: JP
authors.lastname: Thiery
authors.affiliation: Department of Biochemistry and Cancer Biology, University of Toledo, College of Medicine, Health Science Campus, Toledo, OH, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Trumbly
authors.affiliation: State Key Laboratory Of Silkworm Genome Biology, Chongqing, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Fan
authors.affiliation: State Key Laboratory Of Silkworm Genome Biology, Chongqing, China.
authors.forename: Hongjuan
authors.initials: H
authors.lastname: Cui
authors.affiliation: Department of Biochemistry and Cancer Biology, University of Toledo, College of Medicine, Health Science Campus, Toledo, OH, USA.
authors.forename: Kam C
authors.initials: KC
authors.lastname: Yeung
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D018946:Chemokine CCL5 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D005260:Female; D064593:Heterografts; D006801:Humans; D008264:Macrophages / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D049488:Phosphatidylethanolamine Binding Protein / Q000235:genetics / Q000378:metabolism*; D059016:Tumor Microenvironment
chemical_list: C483024:CCL5 protein, human; D018946:Chemokine CCL5; C511482:PEBP1 protein, human; D049488:Phosphatidylethanolamine Binding Protein
keywords: CCL5; RKIP; metastasis suppressor; tumor microenvironment