CCR5 Governs DNA Damage Repair and Breast Cancer Stem Cell Expansion. Cancer Res 2018 Apr 01;78(7):1657-1671
Date
01/24/2018Pubmed ID
29358169Pubmed Central ID
PMC6331183DOI
10.1158/0008-5472.CAN-17-0915Scopus ID
2-s2.0-85047155981 (requires institutional sign-in at Scopus site) 90 CitationsAbstract
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+ 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. Cancer Res; 78(7); 1657-71. ©2018 AACR.
Author List
Jiao X, Velasco-Velázquez MA, Wang M, Li Z, Rui H, Peck AR, Korkola JE, Chen X, Xu S, DuHadaway JB, Guerrero-Rodriguez S, Addya S, Sicoli D, Mu Z, Zhang G, Stucky A, Zhang X, Cristofanilli M, Fatatis A, Gray JW, Zhong JF, Prendergast GC, Pestell RGMESH terms used to index this publication - Major topics in bold
AnimalsAntineoplastic Agents
Breast Neoplasms
CCR5 Receptor Antagonists
Cell Line, Tumor
Cell Proliferation
Cell Transformation, Neoplastic
DNA Damage
DNA Repair
Epithelial Cells
Female
Gene Expression Regulation, Neoplastic
Humans
Mice
Mice, Nude
Neoplasm Transplantation
Neoplastic Stem Cells
Phosphatidylinositol 3-Kinases
Piperazines
Pyrimidines
Receptors, CCR5
Transplantation, Heterologous