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      The CCL5/CCR5 axis promotes metastasis in basal breast cancer

      research-article
      Author(s): 1 , 2 , 3 , *
      Publication date (Electronic):
      Journal: Oncoimmunology
      Publisher: Landes Bioscience
      Keywords: basal breast cancer, CCL5, CCR5, Maraviroc, metastasis, Vicriviroc

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          Abstract

          Recently, we have shown that the CCL5/CCR5 axis is active in patients affected by an aggressive basal subtype of breast cancer. Using preclinical models, we have demonstrated that CCR5 promotes breast cancer invasiveness and metastatic potential, while CCR5 inhibition abrogates them. Thus, CCR5 antagonists may constitute an alternative therapeutic approach for patients affected by metastatic basal breast cancer.

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          Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity.

          Patrick Dorr, Mike Westby, Susan Dobbs … (2005)
          Maraviroc (UK-427,857) is a selective CCR5 antagonist with potent anti-human immunodeficiency virus type 1 (HIV-1) activity and favorable pharmacological properties. Maraviroc is the product of a medicinal chemistry effort initiated following identification of an imidazopyridine CCR5 ligand from a high-throughput screen of the Pfizer compound file. Maraviroc demonstrated potent antiviral activity against all CCR5-tropic HIV-1 viruses tested, including 43 primary isolates from various clades and diverse geographic origin (geometric mean 90% inhibitory concentration of 2.0 nM). Maraviroc was active against 200 clinically derived HIV-1 envelope-recombinant pseudoviruses, 100 of which were derived from viruses resistant to existing drug classes. There was little difference in the sensitivity of the 200 viruses to maraviroc, as illustrated by the biological cutoff in this assay (= geometric mean plus two standard deviations [SD] of 1.7-fold). The mechanism of action of maraviroc was established using cell-based assays, where it blocked binding of viral envelope, gp120, to CCR5 to prevent the membrane fusion events necessary for viral entry. Maraviroc did not affect CCR5 cell surface levels or associated intracellular signaling, confirming it as a functional antagonist of CCR5. Maraviroc has no detectable in vitro cytotoxicity and is highly selective for CCR5, as confirmed against a wide range of receptors and enzymes, including the hERG ion channel (50% inhibitory concentration, >10 microM), indicating potential for an excellent clinical safety profile. Studies in preclinical in vitro and in vivo models predicted maraviroc to have human pharmacokinetics consistent with once- or twice-daily dosing following oral administration. Clinical trials are ongoing to further investigate the potential of using maraviroc for the treatment of HIV-1 infection and AIDS.
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            Expression of CCL5 (RANTES) and CCR5 in prostate cancer.

            Gayle Vaday, Neil Lawrence, Donna Peehl … (2006)
            Expression of the inflammatory chemokine CCL5 (RANTES) by tumor cells is thought to correlate with the progression of several cancers. CCL5 was shown to induce breast cancer cell migration, mediated by the receptor CCR5. A CCR5 antagonist was demonstrated to inhibit experimental breast tumor growth. Recently, CCL5 and CCR5 mRNA expression was reported in prostate cancer (PCa) tissues. Herein, we characterized CCL5 and CCR5 expression in cultures of PCa cells and explored possible functions of CCL5 in PCa progression. Quantitative RT-PCR, ELISA, and immunohistochemical staining were performed to examine CCL5 expression in prostate cell lines. CCR5 expression was measured by flow cytometry. Proliferation and invasion assays were performed to determine potential functions of CCL5 and CCR5 in PCa. Expression of CCL5 mRNA and protein was found in human PCa cell lines (PC-3; DU-145; LNCaP) and primary prostate adenocarcinoma cells. CCL5 and CCR5 were also detected in human PCa tissues. CCR5 expression was demonstrated on the cell surface of PCa cells, as well as in intracellular pools. Incubation with CCL5 (10-100 ng/ml) induced PCa cell proliferation, and the CCR5 antagonist TAK-779 inhibited CCL5-induced proliferation. CCL5 was found to stimulate PCa cell invasion, and TAK-779 blocked the effects of CCL5. In light of evidence that inflammation influences the pathogenesis of PCa, these results suggest that inflammatory chemokines, such as CCL5, expressed by prostate cells may act directly on the growth and survival of PCa cells. Chemokine receptor antagonists may thus block autocrine mechanisms of PCa progression.
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              CCL5 promotes proliferation of MCF-7 cells through mTOR-dependent mRNA translation.

              Thomas T. Murooka, Ramtin Rahbar, Eleanor N. Fish (2009)
              The proliferative capacity of cancer cells is regulated by factors intrinsic to cancer cells and by secreted factors in the microenvironment. Here, we investigated the proto-oncogenic potential of the chemokine receptor, CCR5, in MCF-7 breast cancer cell lines. At physiological levels, CCL5, a ligand for CCR5, enhanced MCF-7.CCR5 proliferation. Treatment with the mTOR inhibitor, rapamycin, inhibited this CCL5-inducible proliferation. Because mTOR directly modulates mRNA translation, we investigated whether CCL5 activation of CCR5 leads to increased translation. CCL5 induced the formation of the eIF4F translation initiation complex through an mTOR-dependent process. Indeed, CCL5 initiated mRNA translation, shown by an increase in high-molecular-weight polysomes. Specifically, we show that CCL5 mediated a rapid up-regulation of protein expression for cyclin D1, c-Myc and Dad-1, without affecting their mRNA levels. Taken together, we describe a mechanism by which CCL5 influences translation of rapamycin-sensitive mRNAs, thereby providing CCR5-positive breast cancer cells with a proliferative advantage.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Oncoimmunology
                Journal ID (iso-abbrev): Oncoimmunology
                Journal ID (publisher-id): ONCI
                Title: Oncoimmunology
                Publisher: Landes Bioscience
                ISSN (Print): 2162-4011
                ISSN (Electronic): 2162-402X
                Publication date (Print): 01 April 2013
                Publication date (Electronic): 01 April 2013
                Publication date PMC-release: 01 April 2013
                Volume: 2
                Issue: 4
                Electronic Location Identifier: e23660
                Affiliations
                [1 ]Departamento de Farmacología; Facultad de Medicina; Universidad Nacional Autónoma de México; Mexico DF, México
                [2 ]Kimmel Cancer Center; Thomas Jefferson University; Philadelphia, PA USA
                [3 ]Department of Cancer Biology; Thomas Jefferson University; Philadelphia, PA USA
                Author notes
                [* ]Correspondence to: Richard G. Pestell, Email: richard.pestell@ 123456jefferson.edu
                Article
                Publisher ID: 2013ONCOIMM0016 Publisher Item ID: 23660
                DOI: 10.4161/onci.23660
                PMC ID: 3654591
                PubMed ID: 23734321
                SO-VID: 97e9fcf1-877b-4f97-aee8-3f47d65cf9c0
                Copyright © Copyright © 2013 Landes Bioscience
                License:

                This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.

                History
                Date received : 17 January 2013
                Date accepted : 18 January 2013
                Categories
                Subject: Author's View

                ScienceOpen disciplines: Immunology
                Keywords: basal breast cancer,ccl5,ccr5,maraviroc,metastasis,vicriviroc
                Data availability:
                ScienceOpen disciplines: Immunology
                Keywords: basal breast cancer, ccl5, ccr5, maraviroc, metastasis, vicriviroc

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