TY - JOUR
T1 - CCR5 Governs DNA damage repair and breast cancer stem cell expansion
AU - Jiao, Xuanmao
AU - Velasco-Velazquez, Marco A.
AU - Wang, Min
AU - Li, Zhiping
AU - Rui, Hallgeir
AU - Peck, Amy R.
AU - Korkola, James E.
AU - Chen, Xuelian
AU - Xu, Shaohua
AU - DuHadaway, James B.
AU - Guerrero-Rodriguez, Sandra
AU - Addya, Sankar
AU - Sicoli, Daniela
AU - Mu, Zhaomei
AU - Zhang, Gang
AU - Stucky, Andres
AU - Zhang, Xi
AU - Cristofanilli, Massimo
AU - Fatatis, Alessandro
AU - Gray, Joe W.
AU - Zhong, Jiang F.
AU - Prendergast, George C.
AU - Pestell, Richard G.
N1 - Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/4/1
Y1 - 2018/4/1
N2 - The functional significance of the chemokine receptor CCR5 in human breast cancer epithelial cells is poorly understood. Here, we report that CCR5 expression in human breast cancer correlates with poor outcome. CCR5 þ breast cancer epithelial cells formed mammospheres and initiated tumors with >60-fold greater efficiency in mice. Reintroduction of CCR5 expression into CCR5-negative breast cancer cells promoted tumor metastases and induced DNA repair gene expression and activity. CCR5 antagonists Maraviroc and Vicriviroc dramatically enhanced cell killing mediated by DNA-damaging chemotherapeutic agents. Single-cell analysis revealed CCR5 governs PI3K/Akt, ribosomal biogenesis, and cell survival signaling. As CCR5 augments DNA repair and is reexpressed selectively on cancerous, but not normal breast epithelial cells, CCR5 inhibitors may enhance the tumor-specific activities of DNA damage response–based treatments, allowing a dose reduction of standard chemotherapy and radiation. Significance: This study offers a preclinical rationale to reposition CCR5 inhibitors to improve the treatment of breast cancer, based on their ability to enhance the tumor-specific activities of DNA-damaging chemotherapies administered in that disease.
AB - The functional significance of the chemokine receptor CCR5 in human breast cancer epithelial cells is poorly understood. Here, we report that CCR5 expression in human breast cancer correlates with poor outcome. CCR5 þ breast cancer epithelial cells formed mammospheres and initiated tumors with >60-fold greater efficiency in mice. Reintroduction of CCR5 expression into CCR5-negative breast cancer cells promoted tumor metastases and induced DNA repair gene expression and activity. CCR5 antagonists Maraviroc and Vicriviroc dramatically enhanced cell killing mediated by DNA-damaging chemotherapeutic agents. Single-cell analysis revealed CCR5 governs PI3K/Akt, ribosomal biogenesis, and cell survival signaling. As CCR5 augments DNA repair and is reexpressed selectively on cancerous, but not normal breast epithelial cells, CCR5 inhibitors may enhance the tumor-specific activities of DNA damage response–based treatments, allowing a dose reduction of standard chemotherapy and radiation. Significance: This study offers a preclinical rationale to reposition CCR5 inhibitors to improve the treatment of breast cancer, based on their ability to enhance the tumor-specific activities of DNA-damaging chemotherapies administered in that disease.
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U2 - 10.1158/0008-5472.CAN-17-0915
DO - 10.1158/0008-5472.CAN-17-0915
M3 - Article
C2 - 29358169
AN - SCOPUS:85047155981
SN - 0008-5472
VL - 78
SP - 1657
EP - 1671
JO - Cancer Research
JF - Cancer Research
IS - 7
ER -