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Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL–RANK signalling

Nature volume 470, pages 548–553 (2011)Cite this article

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Abstract

Inflammatory mechanisms influence tumorigenesis and metastatic progression even in cancers whose aetiology does not involve pre-existing inflammation or infection, such as breast and prostate cancers1. For instance, prostate cancer metastasis is associated with the infiltration of lymphocytes into advanced tumours and the upregulation of two tumour-necrosis-factor family members: receptor activator of nuclear factor-κB (RANK) ligand (RANKL) and lymphotoxin2. But the source of RANKL and its role in metastasis have not been established. RANKL and its receptor RANK control the proliferation of mammary lobuloalveolar cells during pregnancy3 through inhibitor of nuclear factor-κB (IκB) kinase-α (IKK-α)4, a protein kinase that is needed for the self-renewal of mammary cancer progenitors5 and for prostate cancer metastasis2. We therefore examined whether RANKL, RANK and IKK-α are also involved in mammary/breast cancer metastasis. Indeed, RANK signalling in mammary carcinoma cells that overexpress the proto-oncogene Erbb2 (also known as Neu)6, which is frequently amplified in metastatic human breast cancers7,8, was important for pulmonary metastasis. Metastatic spread of Erbb2-transformed carcinoma cells also required CD4+CD25+ T cells, whose major pro-metastatic function was RANKL production. Most RANKL-producing T cells expressed forkhead box P3 (FOXP3), a transcription factor produced by regulatory T cells, and were located next to smooth muscle actin (SMA)+ stromal cells in mouse and human breast cancers. The dependence of pulmonary metastasis on T cells was replaceable by exogenous RANKL, which also stimulated pulmonary metastasis of RANK+ human breast cancer cells. These results are consistent with the adverse impact of tumour-infiltrating CD4+ or FOXP3+ T cells on human breast cancer prognosis9,10 and suggest that the targeting of RANKL–RANK can be used in conjunction with the therapeutic elimination of primary breast tumours to prevent recurrent metastatic disease.

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Figure 1: RANK signalling in mammary carcinoma cells enhances metastasis.
Figure 2: Expression of RANKL in mammary tumours depends on CD4 + T cells.
Figure 3: Tumour-infiltrating CD4 + cells stimulate pulmonary metastasis.
Figure 4: RANKL in human breast cancer.

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  • 23 February 2011

    A correction was made to the Acknowledgements.

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Acknowledgements

We thank L. Coussens for discussions and suggestions, V. Temkin and G. He for advice, and H. Herschman for critical reading. Work was supported by the National Institutes of Health (NIH). W.T. and W.Z. were supported by postdoctoral fellowships from Susan G. Komen for the Cure. A.S. was supported by NIH Asthma Research and Cancer Therapeutic training grants, and S.G. was supported by a research fellowship from the Crohn’s and Colitis Foundation of America. M.K. is an American Cancer Society research professor.

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Author notes

  1. Wei Tan

    Present address: Present address: Pfizer Oncology Research Unit West, San Diego, California 92121, USA.,

  2. Wei Tan and Weizhou Zhang: These authors contributed equally to this work.

Authors and Affiliations

  1. Departments of Pharmacology and Pathology, Laboratory of Gene Regulation and Signal Transduction, University of California San Diego School of Medicine, 9500 Gilman Drive, Mail Code 0723, La Jolla, California 92093, USA,

    Wei Tan, Weizhou Zhang, Amy Strasner, Sergei Grivennikov & Michael Karin

  2. Department of Molecular Oncology, H. Lee Moffitt Cancer Center, Tampa, 33612, Florida, USA

    Jin Q. Cheng

  3. Department of Surgery, University of California San Diego, San Diego, 92103-8220, California, USA

    Robert M. Hoffman

  4. AntiCancer Inc., San Diego, 92111, California, USA

    Robert M. Hoffman

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Contributions

W.T., W.Z., A.S. and M.K. designed the research. W.T., W. Z. and A.S. performed most of the experiments and analysed the data. W.T., W.Z., A.S. and M. K. wrote the manuscript. S.G. performed some of the experiments and analysed their data. J.Q.C. and R.M.H. provided essential reagents, in vivo imaging and technical discussions.

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Correspondence to Michael Karin.

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Tan, W., Zhang, W., Strasner, A. et al. Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL–RANK signalling. Nature 470, 548–553 (2011). https://doi.org/10.1038/nature09707

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