CCR5 Governs DNA Damage Repair and Breast Cancer Stem Cell Expansion

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-...

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Vydáno v:Cancer research (Chicago, Ill.) Ročník 78; číslo 7; s. 1657
Hlavní autoři: Jiao, Xuanmao, Velasco-Velázquez, Marco A, Wang, Min, Li, Zhiping, Rui, Hallgeir, Peck, Amy R, Korkola, James E, Chen, Xuelian, Xu, Shaohua, DuHadaway, James B, Guerrero-Rodriguez, Sandra, Addya, Sankar, Sicoli, Daniela, Mu, Zhaomei, Zhang, Gang, Stucky, Andres, Zhang, Xi, Cristofanilli, Massimo, Fatatis, Alessandro, Gray, Joe W, Zhong, Jiang F, Prendergast, George C, Pestell, Richard G
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 01.04.2018
Témata:
Animals
Antineoplastic Agents - pharmacology
Breast Neoplasms - genetics
Breast Neoplasms - pathology
CCR5 Receptor Antagonists - pharmacology
Cell Line, Tumor
Cell Proliferation - genetics
Cell Transformation, Neoplastic - genetics
DNA Damage - genetics
DNA Repair - immunology
Epithelial Cells - metabolism
Female
Gene Expression Regulation, Neoplastic
Humans
Maraviroc - pharmacology
Mice
Mice, Nude
Neoplasm Transplantation
Neoplastic Stem Cells - metabolism
Phosphatidylinositol 3-Kinases - metabolism
Piperazines - pharmacology
Pyrimidines - pharmacology
Receptors, CCR5 - metabolism
Transplantation, Heterologous
ISSN:1538-7445, 1538-7445
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Shrnutí: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. 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. .
Bibliografie:ObjectType-Article-1
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ISSN:1538-7445
1538-7445
DOI:10.1158/0008-5472.CAN-17-0915