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Cancer Res. 2006 Jun 15;66(12):6327-35.

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

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  • 1Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, MD 20892-5055, USA.


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.

[PubMed - indexed for MEDLINE]
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Images from this publication.See all images (7)Free text

Figure 1. 1D11 decreases 4T1 metastasis to the lung following orthotopic implantation.
Figure 2. Metastatic cells recovered from 1D11-treated lungs show persistent morphological changes in culture and elevated Bsp expression  in vitro  and  in vivo .
Figure 3. TGF-β regulates and is correlated with Bsp expression in 4T1-related cell lines  in vitro .
Figure 4. Bsp knockdown suppresses basal and TGF-β-induced invasion through Matrigel.
Figure 5. Bsp knockdown does not affect induction of MMPs by TGF-β, but does reduce local activation of matrix degrading enzymes.
Figure 6. Bsp protects 4T1 cells from complement-mediated cell lysis.
Figure 7. Knockdown of Bsp suppresses metastasis of 4T1 cells to the lung.
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