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Cancer Lett. 2014 Aug 28;351(1):72-80. doi: 10.1016/j.canlet.2014.05.006. Epub 2014 Jun 2.

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

Author information

1
College of Pharmacy, Ewha Womans University, Seodaemun-gu, Seoul, Republic of Korea.
2
Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Incheon, Republic of Korea.
3
College of Pharmacy, Ewha Womans University, Seodaemun-gu, Seoul, Republic of Korea. Electronic address: yysheen@ewha.ac.kr.

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.

KEYWORDS:

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

PMID:
24887560
DOI:
10.1016/j.canlet.2014.05.006
[Indexed for MEDLINE]

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