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 4

Effect of repertaxin treatment on the breast CSC population in vivo.

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Effect of repertaxin treatment on the breast CSC population in vivo. (A–...
(A–C) For each xenograft, 50,000 cells were injected into the mammary fat pad of mice. (A) Tumor size before and during the course of each indicated treatment (arrow indicates beginning of the treatment). Similar results were observed for each sample (UM2 shown here; see Supplemental Figure 12 for SUM159, MC1, and UM3), with a statistically significant size reduction of the tumor treated with docetaxel alone or in combination with repertaxin compared with the control tumors (P < 0.01). (B and C) Docetaxel-treated tumor showed similar or increase percentage of ALDEFLUOR+ cells compared with the control, whereas repertaxin treatment alone or in combination produced a statistically significant decrease in ALDEFLUOR+ cells (P < 0.01; B). Serial dilutions of cells obtained from these xenografts were implanted in the mammary fat pad of secondary mice, which received no further treatment. Cells from control and docetaxel-treated tumors formed secondary tumors at all dilutions, whereas only higher numbers of cells obtained from xenografts treated with repertaxin alone or in combination were able to generate tumors (P < 0.01; C). (D) Xenotransplants from each group were collected, and immunohistochemistry staining was done. Phospho-FAK, phospho-AKT, and ALDH1 expression was detected in the control and docetaxel-treated tumors, whereas low or no expression was detected in the tumors treated with repertaxin alone or in combination. Nuclear FOXO3A expression was detected in the cells treated with docetaxel and/or with repertaxin (arrowheads denote positive staining). Scale bar: 100 μm. Error bars represent mean ± SD.