CCR5 Governs DNA Damage Repair and Breast Cancer Stem Cell Expansion

Abstract

The functional significance of the chemokine receptor CCR5 in human breast cancer epithelial cells is poorly understood. Here, we report that CCR5 expression in human breast cancer correlates with poor outcome. CCR5 breast cancer epithelial cells formed mammospheres and initiated tumors with >60-fold greater efficiency in mice. Reintroduction of CCR5 expression into CCR5-negative breast cancer cells promoted tumor metastases and induced DNA repair gene expression and activity. CCR5 antagonists Maraviroc and Vicriviroc dramatically enhanced cell killing mediated by DNA-damaging chemotherapeutic agents. Single-cell analysis revealed CCR5 governs PI3K/Akt, ribosomal biogenesis, and cell survival signaling. As CCR5 augments DNA repair and is reexpressed selectively on cancerous, but not normal breast epithelial cells, CCR5 inhibitors may enhance the tumor-specific activities of DNA damage response-based treatments, allowing a dose reduction of standard chemotherapy and radiation. This study offers a preclinical rationale to reposition CCR5 inhibitors to improve the treatment of breast cancer, based on their ability to enhance the tumor-specific activities of DNA-damaging chemotherapies administered in that disease. .

High expression of CCR5 in melanoma enhances epithelial–mesenchymal transition and metastasis via TGFβ1

“…TGFβ also activates non-Smad pathways, such as PI3K/AKT and MAPKs, which mediate the induction of EMT [43,44]. Phosphorylation of AKT, but not MAPKs (p38, Erk and JNK), was significantly attenuated due to CCR5 deficiency ( Figure 6B,C; Supplementary material, Figure S6A), whereas CCL5 stimulation activated AKT (see supplementary material, Figure S6B), consistent with CCR5 effects on AKT signaling in breast cancer cells [45]. GSK3β can be phosphorylated by AKT and promote EMT through upregulating Snail and downregulating E-cadherin [46,47].…”

Chemokines and their Receptors: Multifaceted Roles in Cancer Progression and Potential Value as Cancer Prognostic Markers

“…In addition, CXCR1 blockage reduced CSC properties in clear cell renal cell carcinoma [150], depleted the CSC population, and reduced systemic metastasis development in BC cells [151]. CCR5 + BC cells demonstrated several specific features of CSCs, including increased mammosphere formation, enhanced ability to initiate tumors, and metastatic capacity, as well as improved DNA repair activity [152]. Briefly, chemokines promote tumor metastasis through their hijacked cell migration highway, the establishment of a premetastatic niche, formation of pseudopodia, and induction of EMT and CSC properties.…”

Metabolomics as an Approach to Characterise the Contrasting Roles of CCR5 in the Presence and Absence of Disease

“…[178]. More recently, a study conducted by Jiao et al [179] reported on a possible protective role of CCR5 in breast cancer as investigated in a mouse model. Flow cytometry was used to sort cells according to CCR5 expression.…”

“…The authors showed mice harbouring CCR5 + cells to have an improved activity of pathways involved in DNA repair. Consequently, the authors concluded that DNA damage repair can be induced by the presence of functional CCR5 due to the cell signalling pathways affected [179]. In this context, the CCR5 + cells serve a protective role.…”