Fibulin-3 is a novel TGF-beta pathway inhibitor in the breast cancer microenvironment
Tian,H.; Liu,J.; Chen,J.; Gatza,M. L.; Blobe,G. C.
Source PublicationONCOGENE
AbstractTransforming growth factor-beta (TGF-beta) is an important regulator of breast cancer progression. However, how the breast cancer microenvironment regulates TGF-beta signaling during breast cancer progression remains largely unknown. Here, we identified fibulin-3 as a secreted protein in the breast cancer microenvironment, which efficiently inhibits TGF-beta signaling in both breast cancer cells and endothelial cells. Mechanistically, fibulin-3 interacts with the type I TGF-beta receptor (T beta RI) to block TGF-beta induced complex formation of T beta RI with the type II TGF-beta receptor (T beta RII) and subsequent downstream TGF-beta signaling. Fibulin-3 expression decreases during breast cancer progression, with low fibulin-3 levels correlating with a poorer prognosis. Functionally, high fibulin-3 levels inhibited TGF-beta-induced epithelial-mesenchymal transition (EMT), migration, invasion and endothelial permeability, while loss of fibulin-3 expression/function promoted these TGF-beta-mediated effects. Further, restoring fibulin-3 expression in breast cancer cells inhibited TGF-beta signaling, breast cancer cell EMT, invasion and metastasis in vivo. These studies provide a novel mechanism for how TGF-beta signaling is regulated by the tumor microenvironment, and provide insight into targeting the TGF-beta signaling pathway in human breast cancer patients.
Indexed BySCI
WOS Research AreaBiochemistry & Molecular Biology ; Oncology ; Cell Biology ; Genetics & Heredity
WOS SubjectBiochemistry & Molecular Biology ; Oncology ; Cell Biology ; Genetics & Heredity
WOS IDWOS:000364594300005
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Document Type期刊论文
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Tian,H.,Liu,J.,Chen,J.,et al. Fibulin-3 is a novel TGF-beta pathway inhibitor in the breast cancer microenvironment[J]. ONCOGENE,2015,34(45):5635-5647.
APA Tian,H.,Liu,J.,Chen,J.,Gatza,M. L.,&Blobe,G. C..(2015).Fibulin-3 is a novel TGF-beta pathway inhibitor in the breast cancer microenvironment.ONCOGENE,34(45),5635-5647.
MLA Tian,H.,et al."Fibulin-3 is a novel TGF-beta pathway inhibitor in the breast cancer microenvironment".ONCOGENE 34.45(2015):5635-5647.
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