Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway

Yibin Kang, Wei He, Shaun Tulley, Gaorav P. Gupta, Inna Serganova, Chang Rung Chen, Katia Manova-Todorova, Ronald Blasberg, William L. Gerald, Joan Massagué

Research output: Contribution to journalArticlepeer-review

460 Scopus citations


TGF-β 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-β 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.

Original languageEnglish (US)
Pages (from-to)13909-13914
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number39
StatePublished - Sep 27 2005

All Science Journal Classification (ASJC) codes

  • General


  • IL-11
  • Smad4
  • TGF-β


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