CXCR4 Regulates Growth of Both Primary and Metastatic Breast Cancer

Cancer Research - Tập 64 Số 23 - Trang 8604-8612 - 2004
Matthew C. Smith1, Kathryn E. Luker1, Joel R. Garbow2, Julie L. Prior1, Erin Jackson1, David Piwnica‐Worms1,3, Gary D. Luker1
11Molecular Imaging Center, Mallinckrodt Institute of Radiology, and
23Department of Chemistry, Washington University, St. Louis, Missouri
32Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri; and

Tóm tắt

Abstract The chemokine receptor CXCR4 and its cognate ligand CXCL12 recently have been proposed to regulate the directional trafficking and invasion of breast cancer cells to sites of metastases. However, effects of CXCR4 on the growth of primary breast cancer tumors and established metastases and survival have not been determined. We used stable RNAi to reduce expression of CXCR4 in murine 4T1 cells, a highly metastatic mammary cancer cell line that is a model for stage IV human breast cancer. Using noninvasive bioluminescence and magnetic resonance imaging, we showed that knockdown of CXCR4 significantly limited the growth of orthotopically transplanted breast cancer cells. Mice in which parental 4T1 cells were implanted had progressively enlarging tumors that spontaneously metastasized, and these animals all died from metastatic disease. Remarkably, RNAi of CXCR4 prevented primary tumor formation in some mice, and all mice transplanted with CXCR RNAi cells survived without developing macroscopic metastases. To analyze effects of CXCR4 on metastases to the lung, an organ commonly affected by metastatic breast cancer, we injected tumor cells intravenously and monitored cell growth with bioluminescence imaging. Inhibiting CXCR4 with RNAi, or the specific antagonist AMD3100, substantially delayed the growth of 4T1 cells in the lung, although neither RNAi nor AMD3100 prolonged overall survival in mice with experimental lung metastases. These data indicate that CXCR4 is required to initiate proliferation and/or promote survival of breast cancer cells in vivo and suggest that CXCR4 inhibitors will improve treatment of patients with primary and metastatic breast cancer.

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Cancer Research

Tập 64 Số 23

8604-8612

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