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NF-κB in breast cancer cells promotes osteolytic bone metastasis by inducing osteoclastogenesis via GM-CSF

Nature Medicine volume 13, pages 62–69 (2007)Cite this article

Abstract

Advanced breast cancers frequently metastasize to bone, resulting in osteolytic lesions, yet the underlying mechanisms are poorly understood. Here we report that nuclear factor–κB (NF-κB) plays a crucial role in the osteolytic bone metastasis of breast cancer by stimulating osteoclastogenesis. Using an in vivo bone metastasis model, we found that constitutive NF-κB activity in breast cancer cells is crucial for the bone resorption characteristic of osteolytic bone metastasis. We identified the gene encoding granulocyte macrophage–colony stimulating factor (GM-CSF) as a key target of NF-κB and found that it mediates osteolytic bone metastasis of breast cancer by stimulating osteoclast development. Moreover, we observed that the expression of GM-CSF correlated with NF-κB activation in bone-metastatic tumor tissues from individuals with breast cancer. These results uncover a new and specific role of NF-κB in osteolytic bone metastasis through GM-CSF induction, suggesting that NF-κB is a potential target for the treatment of breast cancer and the prevention of skeletal metastasis.

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Figure 1: Blocking NF-κB inhibits osteolytic bone metastasis of breast cancer in vivo.
Figure 2: Inhibition of breast cancer bone metastasis by IKK2 inhibitors in vivo.
Figure 3: NF-κB-induced CSF2 in breast cancer cells promotes breast cancer bone metastasis in vivo.
Figure 4: GM-CSF is crucial for breast cancer bone metastasis induced by NF-κB in vivo.
Figure 5: Constitutive NF-κB activities in breast cancer cells stimulated osteoclast formation through GM-CSF in vitro.
Figure 6: NF-κB directly stimulates osteoclast formation and promotes bone-metastatic tumor growth in vivo through GM-CSF.

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Acknowledgements

We thank A. Baldwin and D. Guttridge for discussion, T. Guise (University of Virginia) for providing breast cancer cells, and E. Tang, D. Saims, A. Rehman and R. Franceschi for their comments on the manuscript. This study was supported by the US National Institutes of Health (grants DE015618, CA100849 and CA093900).

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Authors and Affiliations

  1. Department of Biologic and Materials Sciences, Laboratory of Molecular Signaling and Apoptosis, University of Michigan, 1011 North University Avenue, Ann Arbor, 48109, Michigan, USA

    Bae Keun Park, Honglai Zhang, Qinghua Zeng, Shaoqiong Chen & Cun-Yu Wang

  2. Department of Urology and Comprehensive Cancer Center, University of Michigan, 1011 North University Avenue, Ann Arbor, 48109, Michigan, USA

    Jinlu Dai & Evan T Keller

  3. Department of Pathology and Comprehensive Cancer Center, University of Michigan, 1011 North University Avenue, Ann Arbor, 48109, Michigan, USA

    Thomas Giordano & Laurie McCauley

  4. Department of Pathology, Henry Ford Health System, Detroit, 48202, Michigan, USA

    Keni Gu, Veena Shah, Lei Pei & Richard J Zarbo

  5. Department of Periodontics and Oral Medicine, School of Dentistry and Medicine, University of Michigan, 1011 North University Avenue, Ann Arbor, 48109, Michigan, USA

    Laurie McCauley

  6. Center for Craniofacial Molecular Biology, School of Dentistry, University of Southern California, Los Angeles, 90033, California, USA

    Songtao Shi

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Contributions

B.K.P., S.C. and C.-Y.W. designed and organized the experiments, performed the animal studies, analyzed the data; generated the figures and wrote the manuscript. H.Z. performed the subcloning. Q.Z., T.G., K.G., V.S., L.P. and R.J.Z. conducted the histological analysis. J.D., S.S., E.T.K. and L.M. performed the animal studies and wrote the manuscript.

Corresponding author

Correspondence to Cun-Yu Wang.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Constitutive NF-κB in breast cancer cells inhibits tumor growth. (PDF 252 kb)

Supplementary Fig. 2

The IKK2 inhibitor VI suppresses subcutaneous tumor growth in vivo. MDA-MB-231 cells (1 × 106) were injected into nude mice subcutaneously and treated with the IKK2 inhibitor VI for 3 weeks, then tumor sizes were measured. (PDF 86 kb)

Supplementary Fig. 3

NF-κB promotes cell invasion in vitro. (PDF 135 kb)

Supplementary Fig. 4

GM-CSF does not activate tumor cells through an antocrine mechanism. (PDF 214 kb)

Supplementary Fig. 5

GM-CSF is highly expressed in bone-metastatic breast tumors from human patients. (PDF 316 kb)

Supplementary Fig. 6

The inhibition of GM-CSF function did not affect tumor cell proliferation. (PDF 43 kb)

Supplementary Fig. 7

GM-CSF-specific antibodies inhibit breast cancer metastasis to bone. (PDF 187 kb)

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Park, B., Zhang, H., Zeng, Q. et al. NF-κB in breast cancer cells promotes osteolytic bone metastasis by inducing osteoclastogenesis via GM-CSF. Nat Med 13, 62–69 (2007). https://doi.org/10.1038/nm1519

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