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Review
. 2023 Sep 8;12(18):2237.
doi: 10.3390/cells12182237.

The Role and Therapeutic Targeting of CCR5 in Breast Cancer

Rasha Hamid  1 , Mustafa Alaziz  1 , Amanpreet S Mahal  1 , Anthony W Ashton  1   2   3 , Niels Halama  4   5 , Dirk Jaeger  4   6 , Xuanmao Jiao  1   2   7 , Richard G Pestell  1   2   7   8
Affiliations
Review

The Role and Therapeutic Targeting of CCR5 in Breast Cancer

Rasha Hamid et al. Cells. .

Abstract

The G-protein-coupled receptor C-C chemokine receptor 5 (CCR5) functions as a co-receptor for the entry of HIV into immune cells. CCR5 binds promiscuously to a diverse array of ligands initiating cell signaling that includes guided migration. Although well known to be expressed on immune cells, recent studies have shown the induction of CCR5 on the surface of breast cancer epithelial cells. The function of CCR5 on breast cancer epithelial cells includes the induction of aberrant cell survival signaling and tropism towards chemo attractants. As CCR5 is not expressed on normal epithelium, the receptor provides a potential useful target for therapy. Inhibitors of CCR5 (CCR5i), either small molecules (maraviroc, vicriviroc) or humanized monoclonal antibodies (leronlimab) have shown anti-tumor and anti-metastatic properties in preclinical studies. In early clinical studies, reviewed herein, CCR5i have shown promising results and evidence for effects on both the tumor and the anti-tumor immune response. Current clinical studies have therefore included combination therapy approaches with checkpoint inhibitors.

Keywords: CCR5; breast cancer; triple-negative breast cancer.

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Conflict of interest statement

R.P. holds ownership interests in CytoDyn, LightSeed, StromaGenesis. ioROC, and EcoGenome, and several patents and submitted patent applications. D.J. and N.H. have intellectual property in the application of CCR5 inhibition in cancer treatment. Other authors declare that they have no conflict of interest.

Figures

Figure 1
Figure 1
Normal physiology of the CCR5-CCL5 axis. CCR5 is shown as a transmembrane receptor linked to the activation Gαi/o, Gαq/11 and Gβγ and their downstream signal pathways.
Figure 2
Figure 2
The activation of PI3K results in the conversion of phosphatidylinositol-2 (PIP2) to phosphatidylinositol-3 (PIP3). PIP3 will recruit a Pleckstrin Homology (PH) domain containing proteins, including Rho-GEFs, PDK1, and Akt, as well as Btk/Itk and PLCγ, to the plasma membrane for activation.
Figure 3
Figure 3
Schematic representation of CCR5 signaling in breast cancer cells. The activation of CCR5 by ligand induces downstream signaling pathways impacting ribosomal biogenesis in breast cancer and induces several signaling pathways, including NF-κB, Akt, and STATs, contributing to protein synthesis, cellular growth, and migration.
Figure 4
Figure 4
Formation of M1 and M2 macrophages in the tumor microenvironment. CCR5 inhibitor maraviroc promoted enrichment of M1 from M2 macrophages.
See this image and copyright information in PMC

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