The role of chemokine receptors in breast cancer metastasis.

Abstract

Metastasis is a multi-step process during which cancer cells disseminate from the primary tumour and establish secondary tumours in distant sites. The mechanisms for organ-specific metastasis are poorly understood, although recent findings suggest the role of a number of chemokine receptors on various cancer cells such as breast CXCR4 as well as CCR7, are a protein-coupled chemokine receptor (apCR) that have proven to be of considerable biological significance, since their expression has been shown on various malignant breast cancer cell lines, tumours and metastases. In this study the expression and function of CXCR4 and CCR7 was examined in a range of human breast cancer cell lines covering a spectrum of malignant and non-malignant phenotypes. The data revealed that while surface levels of CXCR4 and CCR7 were uniform across the entire panel of breast cancer cell lines, only highly invasive cells, metastatic in immunocompromised mice, expressed functional chemokine receptors. Moreover, multiple signalling pathways downstream of a proteins in the highly invasive cells were found to be activated however chemokine treatment failed to activate any of the downstream kinase cascades examined in non-invasive cell lines. For the first time, to the best of our knowledge, chemokine receptor function was demonstrated to be subject to complex and tightly-controlled regulation in epithelial breast cancer cells via differential a protein-receptor complex formation and that this regulation might significantly contribute to the transition from non-metastatic to malignant tumours. Finally, the role of CXCR4 and CCR7 during breast cancer metastasis was verified using a humanised breast cancer metastasis mouse modeL By modulating the expression of chemokine receptors using siRNA-mediated knockdown, metastasis of breast cancer cells to the lungs of SCID mice was dramatically inhibited. In summary, the data point to distinct molecular mechanisms of chemokine receptor activation used by transformed invasive breast epithelial cells which leads to the metastatic spread of these cancer cells to distant sites. Improved understanding of the role of chemokine receptor/ligand interaction in metastasis may lead to novel approaches in the treatment and management of breast cancer as well as other solid tumour malignancies.