bcr675 BCJ Oral presentation <p>Use of mouse models to validate and therapeutically target transforming growth factor beta as an important player in breast cancer progression</p> Wakefield LM Yang Y Dukhanina O Tang B Mamura M Letterio JL Green J Merlino GT Anver MR

Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, Maryland, USA

Laboratory of Molecular Biology, National Cancer Institute, Bethesda, Maryland, USA

Pathology Histotechnology Laboratory, SAIC, NCI at Frederick, Maryland, USA

 Breast Cancer Res <p>24<sup>th </sup>Congress of the International Association for Breast Cancer Research. Advances in human breast cancer research: preclinical models</p> Meeting abstracts <p>24<sup>th </sup>Congress of the International Association for Breast Cancer Research. Advances in human breast cancer research: preclinical models</p> Sacramento, USA 1-5 November 2003 1465-5411 2003 5 Suppl 1 16 10.1186/bcr675 31 10 2003

Transforming growth factor betas (TGF-βs) play key roles in embryogenesis, maintenance of adult homeostasis and response to injury. In epithelial carcinogenesis the TGF-β play complex roles, functioning as tumor suppressors early in the process, but as pro-oncogenic factors in late-stage metastatic disease, when TGF-β ligands are frequently overexpressed. To probe this complexity in vivo, and determine whether TGF-β might be a viable therapeutic target, we developed a transgenic mouse overexpressing a soluble TGF-β antagonist. This antagonist ('SR2F') consisted of the extracellular domain of the type II TGF-β receptor fused to the Fc domain of human IgG1. The SR2F was secreted into the circulation and distributed to all organs except the brain. To determine the effect of this TGF-β antagonist on breast carcinogenesis, the mouse mammary tumor virus (MMTV)-SR2F and wild-type control mice were crossed with the MMTV-neu transgenic mouse model of metastatic breast cancer. The neu/SR2F bigenic mice showed a significant threefold decrease in the incidence of lung metastases compared with mice expressing neu alone. A similar suppression of metastasis was seen in using a tail vein injection model of metastatic melanoma. Importantly, the SR2F did not accelerate primary tumorigenesis, despite the fact that TGF-β has been shown to function as a tumor suppressor in the MMTV-neu model 1. Furthermore, none of the pathology that is usually associated with TGF-β loss, such as autoimmune disease and increased spontaneous tumorigenesis, was observed on prolonged exposure to SR2F. The mechanistic basis for the unexpected selectivity of the SR2F in antagonizing the pro-metastatic effects of TGF-β while sparing effects on tumor suppression and normal homeostasis is currently not clear, but it does not seem to be a dosage effect. Overall, our data suggest that high molecular weight TGF-β antagonists might have promise in the clinic for prevention of metastasis. This study demonstrates the utility of a transgenic approach for testing expensive protein-based therapeutics in long-term realistic models of cancer progression.

 <p/> Siegel Proc Natl Acad Sci USA 2003 100 8430 10.1073/pnas.0932636100 12808151