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Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway.

TGF-beta can signal by means of Smad transcription factors, which are quintessential tumor suppressors that inhibit cell proliferation, and by means of Smad-independent mechanisms, which have been implicated in tumor progression. Although Smad mutations disable this tumor-suppressive pathway in certain cancers, breast cancer cells frequently evade the cytostatic action of TGF-beta while retaining Smad function. Through immunohistochemical analysis of human breast cancer bone metastases and functional imaging of the Smad pathway in a mouse xenograft model, we provide evidence for active Smad signaling in human and mouse bone-metastatic lesions. Genetic depletion experiments further demonstrate that Smad4 contributes to the formation of osteolytic bone metastases and is essential for the induction of IL-11, a gene implicated in bone metastasis in this mouse model system. Activator protein-1 is a key participant in Smad-dependent transcriptional activation of IL-11 and its overexpression in bone-metastatic cells. Our findings provide functional evidence for a switch of the Smad pathway, from tumor-suppressor to prometastatic, in the development of breast cancer bone metastasis.

Pubmed ID: 16172383


  • Kang Y
  • He W
  • Tulley S
  • Gupta GP
  • Serganova I
  • Chen CR
  • Manova-Todorova K
  • Blasberg R
  • Gerald WL
  • Massagu√© J


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

September 27, 2005

Associated Grants

  • Agency: NIGMS NIH HHS, Id: GM07739
  • Agency: NCI NIH HHS, Id: P01-CA94060
  • Agency: NCI NIH HHS, Id: P50-CA86438

Mesh Terms

  • Animals
  • Base Sequence
  • Bone Neoplasms
  • Breast Neoplasms
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Interleukin-11
  • Mice
  • Molecular Sequence Data
  • Neoplasm Transplantation
  • Promoter Regions, Genetic
  • Signal Transduction
  • Transcriptional Activation
  • Transforming Growth Factor beta
  • Tumor Suppressor Proteins