RT Journal Article SR Electronic T1 Inhibition of Growth and Metastasis of Mouse Mammary Carcinoma by Selective Inhibitor of Transforming Growth Factor-β Type I Receptor Kinase In vivo JF Clinical Cancer Research JO Clin Cancer Res FD American Association for Cancer Research SP 4315 OP 4330 DO 10.1158/1078-0432.CCR-06-0162 VO 12 IS 14 A1 Ge, Rongrong A1 Rajeev, Vaishali A1 Ray, Partha A1 Lattime, Edmund A1 Rittling, Susan A1 Medicherla, Satya A1 Protter, Andy A1 Murphy, Alison A1 Chakravarty, Jit A1 Dugar, Sundeep A1 Schreiner, George A1 Barnard, Nicola A1 Reiss, Michael YR 2006 UL http://clincancerres.aacrjournals.org/content/12/14/4315.abstract AB Purpose: Transforming growth factor-β (TGF-β) suppresses tumor development by inhibiting cellular proliferation, inducing differentiation and apoptosis, and maintaining genomic integrity. However, once tumor cells escape from the tumor-suppressive effects of TGF-β, they often constitutively overexpress and activate TGF-β, which may promote tumor progression by enhancing invasion, metastasis, and angiogenesis and by suppressing antitumor immunity. The purpose of this study was to test this hypothesis using TGF-β pathway antagonists. Experimental Design: We examined the effects of selective TGF-β type I receptor kinase inhibitors, SD-093 and SD-208, on two murine mammary carcinoma cell lines (R3T and 4T1) in vitro and in vivo. Results: Both agents blocked TGF-β-induced phosphorylation of the receptor-associated Smads, Smad2 and Smad3, in a dose-dependent manner, with IC50 between 20 and 80 nmol/L. TGF-β failed to inhibit growth of these cell lines but stimulated epithelial-to-mesenchymal transdifferentiation, migration, and invasiveness into Matrigel in vitro. These effects were inhibited by SD-093, indicating that these processes are partly driven by TGF-β. Treatment of syngeneic R3T or 4T1 tumor-bearing mice with orally given SD-208 inhibited primary tumor growth as well as the number and size of metastases. In contrast, SD-208 failed to inhibit R3T tumor growth or metastasis in athymic nude mice. Moreover, in vitro anti-4T1 cell cytotoxic T-cell responses of splenocytes from drug-treated animals were enhanced compared with cells from control animals. In addition, SD-208 treatment resulted in a decrease in tumor angiogenesis. Conclusion: TGF-β type I receptor kinase inhibitors hold promise as novel therapeutic agents for metastatic breast cancer.