CXCR4-CCR7 Heterodimerization Is a Driver of Breast Cancer Progression

Metastatic breast cancer has one of the highest mortality rates among women in western society. Chemokine receptors CXCR4 and CCR7 have been shown to be linked to the metastatic spread of breast cancer, however, their precise function and underlying molecular pathways leading to the acquisition of the pro-metastatic properties remain poorly understood. We demonstrate here that the CXCR4 and CCR7 receptor ligands, CXCL12 and CCL19, cooperatively bind and selectively elicit synergistic signalling responses in invasive breast cancer cell lines as well as primary mammary human tumour cells. Furthermore, for the first time, we have documented the presence of CXCR4-CCR7 heterodimers in advanced primary mammary mouse and human tumours where number of CXCR4-CCR7 complexes directly correlate with the severity of the disease. The functional significance of the CXCR4-CCR7 association was also demonstrated when their forced heterodimerization led to the acquisition of invasive phenotype in non-metastatic breast cancer cells. Taken together, our data establish the CXCR4-CCR7 receptor complex as a new functional unit, which is responsible for the acquisition of breast cancer cell metastatic phenotype and which may serve as a novel biomarker for invasive mammary tumours.

Automated summary

The CXCR4 and CCR7 receptor ligands, CXCL12 and CCL19, cooperatively bind and selectively elicit synergistic signaling responses in invasive breast cancer cell lines and primary mammary human tumor cells. The presence of CXCR4-CCR7 heterodimers in advanced primary mammary mouse and human tumors directly correlates with the severity of the disease, and their forced heterodimerization leads to the acquisition of invasive phenotype in non-metastatic breast cancer cells. These findings establish the CXCR4-CCR7 receptor complex as a new functional unit responsible for the acquisition of breast cancer cell metastatic phenotype and a potential novel biomarker for invasive mammary tumors.