CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts.
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.
Ginestier
Christophe
C
University of Michigan Comprehensive Cancer Center, Department of Internal Medicine/Oncology, Ann Arbor, Michigan 48109-0015, USA. christophe.ginestier@inserm.fr
Liu
Suling
S
Diebel
Mark E
ME
Korkaya
Hasan
H
Luo
Ming
M
Brown
Marty
M
Wicinski
Julien
J
Cabaud
Olivier
O
Charafe-Jauffret
Emmanuelle
E
Birnbaum
Daniel
D
Guan
Jun-Lin
JL
Dontu
Gabriela
G
Wicha
Max S
MS
D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D053222:Fas Ligand Protein / Q000235:genetics; D005260:Female; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000473:pathology* / Q000637:transplantation*; D012333:RNA, Messenger / Q000235:genetics; D023062:Receptors, Interleukin-8A / Q000037:antagonists & inhibitors* / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000473:pathology*; D013449:Sulfonamides / Q000494:pharmacology; D014183:Transplantation, Heterologous / Q000473:pathology
D053222:Fas Ligand Protein; D012333:RNA, Messenger; D023062:Receptors, Interleukin-8A; D013449:Sulfonamides; C490707:reparixin