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

Abstract

<div>Abstract<p>Transforming growth factor βs (TGF-β) 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-β 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-β 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 <i>bone sialoprotein</i> (<i>Bsp</i>). Immunostaining confirmed the loss of Bsp protein in 1D11-treated lung metastases, and TGF-β was shown to regulate and correlate with Bsp expression <i>in vitro</i>. Functionally, knockdown of Bsp in 4T1 cells reduced the ability of TGF-β to induce local collagen degradation and invasion <i>in vitro</i>, and treatment with recombinant Bsp protected 4T1 cells from complement-mediated lysis. Finally, suppression of Bsp in 4T1 cells reduced metastasis <i>in vivo</i>. We conclude that Bsp is a plausible mediator of at least some of the tumor cell–targeted prometastatic activity of TGF-β in this model and that Bsp expression in metastases can be successfully suppressed by systemic treatment with anti-TGF-β antibodies. (Cancer Res 2006; 66(12): 6327-35)</p></div>