Imaging CXCL12-CXCR4 Regulation of Breast Cancer Metastases

Abstract

Abstract : The chemokine receptor CXCR4 and its ligand CXCR12 are proposed to regulate trafficking and invasion of breast cancer cells to sites of metastases. However, effects of CXCR4 on growth of primary breast cancer tumors, established metastases, and survival have not been determined. We used stable RNA interference (RNAi) to reduce expression of CXCR4 in murine 4T1 cells, a metastatic mammary cancer cell. Using bioluminescence and magnetic resonance imaging, we showed that knockdown of CXCR4 significantly limited growth of orthotopically-transplanted breast cancer cells. Mice with parental 4T1 cells had progressively enlarging tumors that spontaneously metastasized, and these animals all died from metastases. RNAi of CXCR4 prevented primary tumor formation in some mice, and all mice with CXCR4 RNAi cells survived without developing macroscopic metastases. To analyze effects of CXCR4 on lung metastases, we injected tumor cells intravenously and monitored cell growth with bioluminescence imaging. Inhibiting CXCR4 with RNAi or the antagonist AMD3100 significantly delayed growth of 4T1 cells in lung, although neither RNAi nor AMD3100 prolonged survival in mice with experimental lung metastases. These data indicate that CXCR4 is required for proliferation and/or survival of breast cancer cells in vivo and suggest that CXCR4 inhibitors will improve treatment of breast cancer.