Inhibition of growth and metastasis of mouse mammary carcinoma by selective inhibitor of transforming growth factor-beta type I receptor kinase in vivo

  • Clin Cancer Res. 2006 Jul 15;12(14 Pt 1):4315-30. doi: 10.1158/1078-0432.CCR-06-0162.
Rongrong Ge  1 ,  Vaishali Rajeev ,  Partha Ray ,  Edmund Lattime ,  Susan Rittling ,  Satya Medicherla ,  Andy Protter ,  Alison Murphy ,  Jit Chakravarty ,  Sundeep Dugar ,  George Schreiner ,  Nicola Barnard ,  Michael Reiss
Affiliations
  • 1. Department of Internal Medicine, The Cancer Institute of New Jersey, New Jersey 08903, USA.
PMID: 16857807 DOI: 10.1158/1078-0432.CCR-06-0162
Abstract

Purpose: Transforming growth factor-beta (TGF-beta) 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-beta, they often constitutively overexpress and activate TGF-beta, 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-beta pathway antagonists.

Experimental design: We examined the effects of selective TGF-beta 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-beta-induced phosphorylation of the receptor-associated Smads, SMAD2 and SMAD3, in a dose-dependent manner, with IC50 between 20 and 80 nmol/L. TGF-beta 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-beta. 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-beta type I receptor kinase inhibitors hold promise as novel therapeutic agents for metastatic breast Cancer.

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