The chemokine receptor CCR7 promotes mammary tumorigenesis through amplification of stem-like cells

• Published in: Oncogene 2016-01, Vol.35 (1), p.105-115
• Main Authors: Boyle, S T, Ingman, W V, Poltavets, V, Faulkner, J W, Whitfield, R J, McColl, S R, Kochetkova, M
• Format: Article
• Language: English
• Subjects: 13/100; 13/31; 631/67/1347; 64/110; Animals; Apoptosis; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer cells; Cell Biology; Cell Line, Tumor; Cell receptors; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Development and progression; Disease Models, Animal; Female; Genetic aspects; Health aspects; Human Genetics; Humans; Internal Medicine; Male; Mammary Glands, Animal - metabolism; Mammary Glands, Animal - pathology; Mammary Glands, Human - metabolism; Mammary Glands, Human - pathology; Mammary Neoplasms, Experimental - genetics; Mammary Neoplasms, Experimental - metabolism; Mammary Neoplasms, Experimental - pathology; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Mice, Knockout; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Oncology; original-article; Receptors, CCR7 - deficiency; Receptors, CCR7 - genetics; Receptors, CCR7 - metabolism; Rodents; Stem cells; Tumors
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2015.66

The chemokine receptor CCR7 is widely implicated in breast cancer pathobiology. Although recent reports correlated high CCR7 levels with more advanced tumor grade and poor prognosis, limited in vivo data are available regarding its specific function in mammary gland neoplasia and the underlying mechanisms involved. To address these questions we generated a bigenic mouse model of breast cancer combined with CCR7 deletion, which revealed that CCR7 ablation results in a considerable delay in tumor onset as well as significantly reduced tumor burden. Importantly, CCR7 was found to exert its function by regulating mammary cancer stem-like cells in both murine and human tumors. In vivo experiments showed that loss of CCR7 activity either through deletion or pharmacological antagonism significantly decreased functional pools of stem-like cells in mouse primary mammary tumors, providing a mechanistic explanation for the tumor-promoting role of this chemokine receptor. These data characterize the oncogenic properties of CCR7 in mammary epithelial neoplasia and point to a new route for therapeutic intervention to target evasive cancer stem cells.