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Bone Sialoprotein Mediates the Tumor Cell–Targeted Prometastatic Activity of Transforming Growth Factor ß in a Mouse Model of Breast Cancer

¹ Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute; ² Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, Bethesda, Maryland; ³ Division of Geriatrics, Department of Medicine, Johns Hopkins University, Baltimore, Maryland; and ⁴ Genzyme Corporation, Framingham, Massachusetts

Requests for reprints: Lalage M. Wakefield, Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Room C629, Building 41, 41 Library Drive, MSC 5055, Bethesda, MD 20892-5055. Phone: 301-496-8351; Fax: 301-496-8395; E-mail: wakefiel{at}dce41.nci.nih.gov.

Transforming growth factor ßs (TGF-ß) 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-ß 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-ß 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-ß was shown to regulate and correlate with Bsp expression in vitro. Functionally, knockdown of Bsp in 4T1 cells reduced the ability of TGF-ß 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-ß in this model and that Bsp expression in metastases can be successfully suppressed by systemic treatment with anti-TGF-ß antibodies. (Cancer Res 2006; 66(12): 6327-35)

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