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

Abstract

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.

• Authors: Jeong-Seok Nam, Adam M Suchar, Mi-Jin Kang, Christina H Stuelten, Binwu Tang, Aleksandra M Michalowska, Larry W Fisher, Neal S Fedarko, Alka Jain, Jan Pinkas, Scott Lonning, Lalage M Wakefield
• Journal: Cancer research (Cancer Res) Vol. 66 Issue 12 Pg. 6327-35 (Jun 15 2006) ISSN: 0008-5472 [Print] United States
• PMID: 16778210 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

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

Topics

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