CCR5 Governs DNA damage repair and breast cancer stem cell expansion

Xuanmao Jiao, Marco A. Velasco-Velazquez, Min Wang, Zhiping Li, Hallgeir Rui, Amy R. Peck, James E. Korkola, Xuelian Chen, Shaohua Xu, James B. DuHadaway, Sandra Guerrero-Rodriguez, Sankar Addya, Daniela Sicoli, Zhaomei Mu, Gang Zhang, Andres Stucky, Xi Zhang, Massimo Cristofanilli, Alessandro Fatatis, Joe W. GrayJiang F. Zhong, George C. Prendergast, Richard G. Pestell*

*Corresponding author for this work

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1657-1671
Number of pages15
JournalCancer Research
Volume78
Issue number7
DOIs
StatePublished - Apr 1 2018

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Jiao, X., Velasco-Velazquez, M. A., Wang, M., Li, Z., Rui, H., Peck, A. R., Korkola, J. E., Chen, X., Xu, S., DuHadaway, J. B., Guerrero-Rodriguez, S., Addya, S., Sicoli, D., Mu, Z., Zhang, G., Stucky, A., Zhang, X., Cristofanilli, M., Fatatis, A., ... Pestell, R. G. (2018). CCR5 Governs DNA damage repair and breast cancer stem cell expansion. Cancer Research, 78(7), 1657-1671. https://doi.org/10.1158/0008-5472.CAN-17-0915