CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts
Christophe Ginestier, … , Gabriela Dontu, Max S. Wicha
Christophe Ginestier, … , Gabriela Dontu, Max S. Wicha
Published January 4, 2010
Citation Information: J Clin Invest. 2010;120(2):485-497. https://doi.org/10.1172/JCI39397.
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Research Article Oncology

CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts

Abstract

Recent evidence suggests that breast cancer and other solid tumors possess a rare population of cells capable of extensive self-renewal that contribute to metastasis and treatment resistance. We report here the development of a strategy to target these breast cancer stem cells (CSCs) through blockade of the IL-8 receptor CXCR1. CXCR1 blockade using either a CXCR1-specific blocking antibody or repertaxin, a small-molecule CXCR1 inhibitor, selectively depleted the CSC population in 2 human breast cancer cell lines in vitro. Furthermore, this was followed by the induction of massive apoptosis in the bulk tumor population via FASL/FAS signaling. The effects of CXCR1 blockade on CSC viability and on FASL production were mediated by the FAK/AKT/FOXO3A pathway. In addition, repertaxin was able to specifically target the CSC population in human breast cancer xenografts, retarding tumor growth and reducing metastasis. Our data therefore suggest that CXCR1 blockade may provide a novel means of targeting and eliminating breast CSCs.

Authors

Christophe Ginestier, Suling Liu, Mark E. Diebel, Hasan Korkaya, Ming Luo, Marty Brown, Julien Wicinski, Olivier Cabaud, Emmanuelle Charafe-Jauffret, Daniel Birnbaum, Jun-Lin Guan, Gabriela Dontu, Max S. Wicha

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Figure 5

Repertaxin treatment reduces the development of systemic metastasis.

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Repertaxin treatment reduces the development of systemic metastasis. (A–...
(A–C) To evaluate the effect of repertaxin treatment on metastasis formation, we infected HCC1954, SUM159, and MDA-MB-453 breast cancer cell lines with a lentivirus expressing luciferase, and inoculated 250,000 luciferase-infected cells into NOD/SCID mice via intracardial injection. Mice were treated 12 hours after intracardiac injection with either s.c. injection of saline solution or s.c. injection of 15 mg/kg repertaxin twice daily for 28 days. Metastasis formation was monitored using bioluminescence imaging. Quantification of the normalized photon flux, measured at weekly intervals following inoculation, revealed a statistically significant decrease (P < 0.01) in metastasis formation in repertaxin-treated compared with saline controls for mice inoculated with HCC1954 (A) or SUM159 (B) cells. In contrast, repertaxin treatment did not have any effect on metastasis formation for the mice injected with MDA-MB-453 (C) cells. (D) Histologic confirmation, by H&E staining, of metastasis in bone and soft tissue resulting from mice not treated with repertaxin. Scale bar: 100 μm. Error bars represent mean ± SD.