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

Oncogene volume 35, pages 105–115 (2016)Cite this article

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Abstract

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.

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Acknowledgements

We are grateful to Dr Timothy Proudman and Dr Pallave Dasari from the Queen Elizabeth Hospital for supply of normal human breast tissue and Dr Deepak Dhatrak of the Department of Anatomical Pathology at SA Pathology for procurement of human breast cancer samples. We would also like to sincerely thank Professor Angel Lopez for critical reading of the manuscript, and Dr Michael Samuel and Ms Natasha Pyne for assistance with immunohistochemistry. This work was supported by an NHMRC project grant. WVI is a National Breast Cancer Foundation/The QEH Research Foundation Fellow.

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Authors and Affiliations

  1. Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, South Australia, Australia

    S T Boyle, V Poltavets, J W Faulkner, S R McColl & M Kochetkova

  2. The Robinson Institute, University of Adelaide, Adelaide, South Australia, Australia,

    W V Ingman

  3. Discipline of Surgery, School of Medicine, The Queen Elizabeth Hospital, University of Adelaide, Adelaide, South Australia, Australia,

    W V Ingman

  4. Breast, Endocrine and Surgical Oncology Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia,

    R J Whitfield

  5. School of Medicine, University of Adelaide, Adelaide, South Australia, Australia,

    R J Whitfield

  6. Centre for Molecular Pathology, University of Adelaide, Adelaide, South Australia, Australia,

    S R McColl

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  1. S T Boyle
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Correspondence to M Kochetkova.

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Boyle, S., Ingman, W., Poltavets, V. et al. The chemokine receptor CCR7 promotes mammary tumorigenesis through amplification of stem-like cells. Oncogene 35, 105–115 (2016). https://doi.org/10.1038/onc.2015.66

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  • DOI: https://doi.org/10.1038/onc.2015.66

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