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–B (NF-B) 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-B 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-B 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-B activation in bone-metastatic tumor tissues from individuals with breast cancer. These results uncover a new and specific role of NF-B in osteolytic bone metastasis through GM-CSF induction, suggesting that NF-B is a potential target for the treatment of breast cancer and the prevention of skeletal metastasis.

1. Laboratory of Molecular Signaling and Apoptosis, Department of Biologic and Materials Sciences, University of Michigan, 1011 North University Avenue, Ann Arbor, Michigan 48109, USA.
2. Department of Urology and Comprehensive Cancer Center, University of Michigan, 1011 North University Avenue, Ann Arbor, Michigan 48109, USA.
3. Department of Pathology and Comprehensive Cancer Center, University of Michigan, 1011 North University Avenue, Ann Arbor, Michigan 48109, USA.
4. Department of Pathology, Henry Ford Health System, Detroit, Michigan 48202, USA.
5. Department of Periodontics and Oral Medicine, School of Dentistry and Medicine, University of Michigan, 1011 North University Avenue, Ann Arbor, Michigan 48109, USA.
6. Center for Craniofacial Molecular Biology, School of Dentistry, University of Southern California, Los Angeles, California 90033, USA.

Correspondence to: Cun-Yu Wang¹ e-mail: cunywang@umich.edu

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