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

Nat Med. 2007 Jan;13(1):62-9. doi: 10.1038/nm1519. Epub 2006 Dec 10.


Advanced breast cancers frequently metastasize to bone, resulting in osteolytic lesions, yet the underlying mechanisms are poorly understood. Here we report that nuclear factor-kappaB (NF-kappaB) 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-kappaB 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-kappaB 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-kappaB activation in bone-metastatic tumor tissues from individuals with breast cancer. These results uncover a new and specific role of NF-kappaB in osteolytic bone metastasis through GM-CSF induction, suggesting that NF-kappaB is a potential target for the treatment of breast cancer and the prevention of skeletal metastasis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blotting, Northern
  • Blotting, Western
  • Bone Neoplasms / chemically induced*
  • Bone Neoplasms / secondary
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cytokine Receptor Common beta Subunit / genetics
  • Cytokine Receptor Common beta Subunit / metabolism
  • Electrophoretic Mobility Shift Assay
  • Female
  • Gene Expression Regulation, Neoplastic
  • Granulocyte-Macrophage Colony-Stimulating Factor / adverse effects*
  • Granulocyte-Macrophage Colony-Stimulating Factor / genetics
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Humans
  • Mammary Neoplasms, Experimental / drug therapy
  • Mammary Neoplasms, Experimental / metabolism
  • Mammary Neoplasms, Experimental / pathology
  • Mice
  • Mice, SCID
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism*
  • Osteoclasts / drug effects*
  • Osteoclasts / metabolism
  • Osteoclasts / pathology
  • Osteogenesis / drug effects
  • RNA Interference
  • Xenograft Model Antitumor Assays


  • Cytokine Receptor Common beta Subunit
  • NF-kappa B
  • Granulocyte-Macrophage Colony-Stimulating Factor