Bone sialoprotein mediates the tumor cell-targeted prometastatic activity of transforming growth factor beta in a mouse model of breast cancer

Cancer Res. 2006 Jun 15;66(12):6327-35. doi: 10.1158/0008-5472.CAN-06-0068.


Transforming growth factor betas (TGF-beta) play a dual role in carcinogenesis, functioning as tumor suppressors early in the process, and then switching to act as prometastatic factors in late-stage disease. We have previously shown that high molecular weight TGF-beta antagonists can suppress metastasis without the predicted toxicities. To address the underlying mechanisms, we have used the 4T1 syngeneic mouse model of metastatic breast cancer. Treatment of mice with a monoclonal anti-TGF-beta antibody (1D11) significantly suppressed metastasis of 4T1 cells to the lungs. When metastatic 4T1 cells were recovered from lungs of 1D11-treated and control mice, the most differentially expressed gene was found to be bone sialoprotein (Bsp). Immunostaining confirmed the loss of Bsp protein in 1D11-treated lung metastases, and TGF-beta was shown to regulate and correlate with Bsp expression in vitro. Functionally, knockdown of Bsp in 4T1 cells reduced the ability of TGF-beta to induce local collagen degradation and invasion in vitro, and treatment with recombinant Bsp protected 4T1 cells from complement-mediated lysis. Finally, suppression of Bsp in 4T1 cells reduced metastasis in vivo. We conclude that Bsp is a plausible mediator of at least some of the tumor cell-targeted prometastatic activity of TGF-beta in this model and that Bsp expression in metastases can be successfully suppressed by systemic treatment with anti-TGF-beta antibodies.

Publication types

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

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / physiology
  • Collagen / metabolism
  • Disease Models, Animal
  • Down-Regulation
  • Female
  • Gene Expression Regulation, Neoplastic
  • Integrin-Binding Sialoprotein
  • Lung Neoplasms / prevention & control
  • Lung Neoplasms / secondary
  • Mammary Neoplasms, Experimental / genetics
  • Mammary Neoplasms, Experimental / metabolism*
  • Mammary Neoplasms, Experimental / pathology*
  • Mammary Neoplasms, Experimental / therapy
  • Mice
  • Mice, Inbred BALB C
  • Neoplasm Metastasis
  • Sialoglycoproteins / biosynthesis*
  • Sialoglycoproteins / genetics
  • Transforming Growth Factor beta / antagonists & inhibitors*
  • Transforming Growth Factor beta / biosynthesis
  • Transforming Growth Factor beta / immunology


  • Antibodies, Monoclonal
  • Ibsp protein, mouse
  • Integrin-Binding Sialoprotein
  • Sialoglycoproteins
  • Transforming Growth Factor beta
  • Collagen