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Involvement of chemokine receptors in breast cancer metastasis

Abstract

Breast cancer is characterized by a distinct metastatic pattern involving the regional lymph nodes, bone marrow, lung and liver. Tumour cell migration and metastasis share many similarities with leukocyte trafficking, which is critically regulated by chemokines and their receptors. Here we report that the chemokine receptors CXCR4 and CCR7 are highly expressed in human breast cancer cells, malignant breast tumours and metastases. Their respective ligands CXCL12/SDF-1α and CCL21/6Ckine exhibit peak levels of expression in organs representing the first destinations of breast cancer metastasis. In breast cancer cells, signalling through CXCR4 or CCR7 mediates actin polymerization and pseudopodia formation, and subsequently induces chemotactic and invasive responses. In vivo, neutralizing the interactions of CXCL12/CXCR4 significantly impairs metastasis of breast cancer cells to regional lymph nodes and lung. Malignant melanoma, which has a similar metastatic pattern as breast cancer but also a high incidence of skin metastases, shows high expression levels of CCR10 in addition to CXCR4 and CCR7. Our findings indicate that chemokines and their receptors have a critical role in determining the metastatic destination of tumour cells.

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Figure 1: Expression of chemokine receptors in human tumour cells.
Figure 2: Expression of CCR7 and CXCR4 in breast cancer.
Figure 3: F-actin polymerization in human breast carcinoma cells.
Figure 4: Chemokine-mediated migration and invasion of breast carcinoma cells.
Figure 5: Migration of breast carcinoma cells in response to organ-derived proteins.
Figure 6: Expression of human CXCR4 and human HPRT in the MDA-MB-231 breast cancer metastasis model.
Figure 7: Effect of CXCR4-neutralization on metastasis in vivo.

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Acknowledgements

We thank R. M. Barcenas for technical assistance; S. Ulloa and K. Smith for help procuring tissue samples; and D. J. Ruiter, I. J. Fidler and D. Schadendorf for the melanoma cell lines. We are grateful to R. de Waal Malefyt for establishing the quantitative RT–PCR at the DNAX Research Institute, and H. Kanzler, T. Hauser and L. Bakker for critical comments on the manuscript. B.H. was supported by a grant from the Deutsche Forschungsgemeinschaft. DNAX Research Institute is supported by the Schering-Plough Corporation.

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Correspondence to Albert Zlotnik.

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Müller, A., Homey, B., Soto, H. et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 410, 50–56 (2001). https://doi.org/10.1038/35065016

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