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

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

Research output: Contribution to journalArticlepeer-review

Abstract

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 bone sialoprotein (Bsp). Immunostaining confirmed the loss of Bsp protein in 1D11-treated lung metastases, and TGF-β was shown to regulate and correlate with Bsp expression in vitro. Functionally, knockdown of Bsp in 4T1 cells reduced the ability of TGF-β 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-β in this model and that Bsp expression in metastases can be successfully suppressed by systemic treatment with anti-TGF-β antibodies.

Original languageEnglish (US)
Pages (from-to)6327-6335
Number of pages9
JournalCancer Research
Volume66
Issue number12
DOIs
StatePublished - Jun 15 2006

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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