title: An novel inhibitor of TGF-β type I receptor, IN-1130, blocks breast cancer lung metastasis through inhibition of epithelial-mesenchymal transition.
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.
authors.affiliation: College of Pharmacy, Ewha Womans University, Seodaemun-gu, Seoul, Republic of Korea.
authors.forename: Chul-Yong
authors.initials: CY
authors.lastname: Park
authors.affiliation: College of Pharmacy, Ewha Womans University, Seodaemun-gu, Seoul, Republic of Korea.
authors.forename: Kyung Nan
authors.initials: KN
authors.lastname: Min
authors.affiliation: College of Pharmacy, Ewha Womans University, Seodaemun-gu, Seoul, Republic of Korea.
authors.forename: Jee-Yeon
authors.initials: JY
authors.lastname: Son
authors.affiliation: College of Pharmacy, Ewha Womans University, Seodaemun-gu, Seoul, Republic of Korea.
authors.forename: So-Yeon
authors.initials: SY
authors.lastname: Park
authors.affiliation: Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Incheon, Republic of Korea.
authors.forename: Jeong-Seok
authors.initials: JS
authors.lastname: Nam
authors.affiliation: College of Pharmacy, Ewha Womans University, Seodaemun-gu, Seoul, Republic of Korea.
authors.forename: Dae-Kee
authors.initials: DK
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Ewha Womans University, Seodaemun-gu, Seoul, Republic of Korea. Electronic address: yysheen@ewha.ac.kr.
authors.forename: Yhun Yhong
authors.initials: YY
authors.lastname: Sheen
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008168:Lung / Q000473:pathology; D008175:Lung Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D021381:Protein Transport; D011810:Quinoxalines / Q000494:pharmacology*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology; D047368:Tumor Burden / Q000187:drug effects
chemical_list: C530153:3-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)benzamide; D007093:Imidazoles; D011810:Quinoxalines; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse
keywords: ALK5; Breast cancer; IN-1130; Metastasis; Transforming growth factor-β (TGF-β)