An novel inhibitor of TGF-β type I receptor, IN-1130, blocks breast cancer lung metastasis through inhibition of epithelial-mesenchymal transition

Chul Yong Park, Kyung Nan Min, Jee Yeon Son, So Yeon Park, Jeong Seok Nam, Dae Kee Kim, Yhun Yhong Sheen

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

TGF-β signaling plays an important role in breast cancer progression and metastasis. Epithelial-mesenchymal transition (EMT) is an important step in the progression of solid tumors to metastatic disease. We previously reported that IN-1130, a novel transforming growth factor-β type I receptor kinase (ALK5) inhibitor, suppressed renal fibrosis in obstructive nephropathy (Moon et al., 2006). Here, we show that IN-1130 suppressed EMT and the lung metastasis of mammary tumors in mouse models. Treating human and mouse cell lines with IN-1130 inhibited TGF-β-mediated transcriptional activation, the phosphorylation and nuclear translocation of Smad2, and TGF-β-induced-EMT, which induces morphological changes in epithelial cells. Additionally, we demonstrated that IN-1130 blocked TGF-β-induced 4T1 mammary cancer cell migration and invasion. The TGF-β-mediated increase in matrix metalloproteinase (MMP)-2 and MMP-9 expression was restored by IN-1130 co-treatment with TGF-β in human epithelial cells and in 4T1 cells. Furthermore, we found that lung metastasis from primary breast cancer was inhibited by IN-1130 in both 4T1-xenografted BALB/c mice and MMTV/c-Neu transgenic mice without any change in primary tumor volume. IN-1130 prolonged the life span of tumor-bearing mice. In summary, this study indicated that IN-1130 has therapeutic potential for preventing breast cancer metastasis to the lung.

Original languageEnglish
Pages (from-to)72-80
Number of pages9
JournalCancer Letters
Volume351
Issue number1
DOIs
StatePublished - 28 Aug 2014

Keywords

  • ALK5
  • Breast cancer
  • IN-1130
  • Metastasis
  • Transforming growth factor-β (TGF-β)

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