title: Fibulin-3 is a novel TGF-β pathway inhibitor in the breast cancer microenvironment.
abstract: Transforming growth factor-β (TGF-β) is an important regulator of breast cancer progression. However, how the breast cancer microenvironment regulates TGF-β 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-β signaling in both breast cancer cells and endothelial cells. Mechanistically, fibulin-3 interacts with the type I TGF-β receptor (TβRI) to block TGF-β induced complex formation of TβRI with the type II TGF-β receptor (TβRII) and subsequent downstream TGF-β 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-β-induced epithelial-mesenchymal transition (EMT), migration, invasion and endothelial permeability, while loss of fibulin-3 expression/function promoted these TGF-β-mediated effects. Further, restoring fibulin-3 expression in breast cancer cells inhibited TGF-β signaling, breast cancer cell EMT, invasion and metastasis in vivo. These studies provide a novel mechanism for how TGF-β signaling is regulated by the tumor microenvironment, and provide insight into targeting the TGF-β signaling pathway in human breast cancer patients.
authors.affiliation: Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, NC, USA.
authors.forename: H
authors.initials: H
authors.lastname: Tian
authors.affiliation: Department of Biochemistry, Duke University Medical Center, Durham, NC, USA.|State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan, PR China.
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.affiliation: Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, NC, USA.
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Gatza
authors.affiliation: Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, NC, USA.|Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.
authors.forename: G C
authors.initials: GC
authors.lastname: Blobe
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D059016:Tumor Microenvironment
chemical_list: C119630:EFEMP1 protein, human; D016326:Extracellular Matrix Proteins; D009363:Neoplasm Proteins; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II
references.citation: Cell. 1992 Dec 11;71(6):1003-14
references.pmid: 1333888
references.citation: Cold Spring Harb Perspect Biol. 2011 Jan;3(1):a003277
references.pmid: 20810549
references.citation: Curr Opin Cell Biol. 1996 Apr;8(2):139-45
references.pmid: 8791413
references.citation: Nature. 1997 Dec 4;390(6659):465-71
references.pmid: 9393997
references.citation: Annu Rev Biochem. 1998;67:753-91
references.pmid: 9759503
references.citation: Cell. 1998 Dec 11;95(6):737-40
references.pmid: 9865691
references.citation: Clin Cancer Res. 2005 Jan 15;11(2 Pt 2):937s-43s
references.pmid: 15701890
references.citation: Trends Mol Med. 2005 Jul;11(7):336-40
references.pmid: 15961345
references.citation: Nature. 2005 Jul 28;436(7050):518-24
references.pmid: 16049480
references.citation: Cytokine Growth Factor Rev. 2006 Oct;17(5):325-37
references.pmid: 16931107
references.citation: J Clin Invest. 2007 Jan;117(1):206-17
references.pmid: 17160136
references.citation: Ann N Y Acad Sci. 2006 Nov;1089:119-26
references.pmid: 17261761
references.citation: J Biol Chem. 2007 Apr 20;282(16):11805-16
references.pmid: 17324935
references.citation: Front Biosci. 2007;12:4393-401
references.pmid: 17485383
references.citation: Oncogene. 2008 Oct 6;27(45):5904-12
references.pmid: 18836471
references.citation: Int J Cancer. 2009 Apr 1;124(7):1727-35
references.pmid: 19115204
references.citation: Nat Protoc. 2009;4(8):1202-15
references.pmid: 19644460
references.citation: Cell Cycle. 2009 Oct 15;8(20):3319-27
references.pmid: 19806012
references.citation: Biol Chem. 2009 Dec;390(12):1293-302
references.pmid: 19804359
references.citation: Cold Spring Harb Perspect Biol. 2010 Aug;2(8):a003186
references.pmid: 20554705
references.citation: J Pathol. 2010 Dec;222(4):367-79
references.pmid: 20927779
references.citation: Biochim Biophys Acta. 2011 Feb;1813(2):308-14
references.pmid: 21167870
references.citation: Crit Rev Oncog. 1999;10(4):303-60
references.pmid: 10654929
references.citation: Trends Biochem Sci. 2000 Feb;25(2):64-70
references.pmid: 10664585
references.citation: J Clin Invest. 2003 Oct;112(7):1116-24
references.pmid: 14523048
references.citation: Nature. 2003 Oct 9;425(6958):577-84
references.pmid: 14534577
references.citation: EMBO Rep. 2003 Dec;4(12):1127-31
references.pmid: 14647206
references.citation: Breast Cancer. 2012 Apr;19(2):118-24
references.pmid: 22139728
references.citation: Cancer Res. 2012 Aug 1;72(15):3873-85
references.pmid: 22665268
references.citation: Cell. 2012 Aug 17;150(4):764-79
references.pmid: 22901808
references.citation: Eur J Cancer. 2013 May;49(8):1845-59
references.pmid: 23453937
references.citation: J Mammary Gland Biol Neoplasia. 2011 Jun;16(2):97-108
references.pmid: 21494783
references.citation: Cancer Metastasis Rev. 2013 Jun;32(1-2):303-15
references.pmid: 23114846
references.citation: Clin Cancer Res. 2011 Jul 1;17(13):4523-30
references.pmid: 21571867
references.citation: Neoplasma. 2011;58(5):441-8
references.pmid: 21744999
references.citation: J Clin Invest. 2011 Oct;121(10):3804-9
references.pmid: 21965337
references.citation: Int J Oncol. 2012 Jan;40(1):130-8
references.pmid: 21904773
references.citation: Int J Oncol. 2012 Feb;40(2):402-8
references.pmid: 21901248
references.citation: Cell Tissue Res. 2012 Jan;347(1):73-84
references.pmid: 21845401
references.citation: Breast Cancer Res. 2011;13(6):227
references.pmid: 22078026
references.citation: Pathol Oncol Res. 2012 Apr;18(2):263-70
references.pmid: 21796503
references.citation: PLoS One. 2013;8(8):e70511
references.pmid: 23936443
references.citation: J Clin Invest. 2013 Sep;123(9):3925-40
references.pmid: 23925295
references.citation: PLoS One. 2013;8(12):e84256
references.pmid: 24391924
references.citation: Carcinogenesis. 2014 Aug;35(8):1707-16
references.pmid: 24480807
references.citation: Cancer Cell. 2004 Jul;6(1):17-32
references.pmid: 15261139
references.citation: Cancer Res. 1992 Mar 15;52(6):1399-405
references.pmid: 1540948
references.citation: J Biol Chem. 1992 Mar 25;267(9):5927-30
references.pmid: 1556106
references.citation: Cell. 1996 Jun 28;85(7):947-50
references.pmid: 8674122