Effects of CCL5 on the biological behavior of breast cancer and the mechanisms of its interaction with tumor-associated macrophages

The recurrence and metastasis of breast cancer limit the effectiveness of clinical treatments, making them important issues for clinicians to address. Tumor-associated macrophages (TAMs) contribute to regulating the immune system. C-C motif chemokine ligand 5 (CCL5) is an inflammatory chemokine that promotes chemotaxis on cells involved in the immune/inflammatory response. Breast cancer cells that secrete CCL5 act on THP-1 cells, influencing the invasion and metastasis of tumors. However, knowledge remains limited regarding the mechanism underlying the effects of CCL5 on breast cancer cells and TAMs, as well as the mechanisms promoting the migration and invasion of breast cancer. The present study demonstrated that the positive expression of CCL5 was associated with lymph node status and tumor-node-metastasis stage. Treatment with ≥20 ng/ml CCL5 significantly promoted the migration and invasion of MCF-7 and MDA-MB-231 cells. CCL5-small interfering RNA intervention significantly decreased the migration and invasion of the two cell types. In vitro, THP-1 cells were successfully induced to become TAMs, which were then recruited via the chemotactic effects of CCL5. This process was achieved through the co-stimulation of phorbol-12-myristate-13- acetate, interleukin-4 (IL-4) and IL-13. The nuclear factor-κB (NF-κB) signaling pathway was activated to regulate EMT, as well as the migration and invasion process of MCF-7 cells, when co-cultured with TAMs. We also reported that blocking the expression of CCL5 in vivo may significantly inhibit the growth of human breast cancer xenografts. Therefore, targeting CCL5 may be considered as a novel therapeutic strategy for suppressing the invasion and metastasis of breast cancer.