title: Binding of αvβ1 and αvβ6 integrins to tenascin-C induces epithelial-mesenchymal transition-like change of breast cancer cells.
abstract: Tenascin-C (TNC), a large hexameric extracellular glycoprotein, is a pleiotropic molecule with multiple domains binding to a variety of receptors mediating a wide range of cellular functions. We earlier reported that TNC induces epithelial-mesenchymal transition (EMT)-like change in breast cancer cells. In the present study, we clarified TNC receptor involvement in this process. Among integrins previously reported as TNC receptors, substantial expression of αv, α2, β1 and β6 subunits was detected by quantitative PCR and immunoblotting in MCF-7 cells. Integrin β6 mRNA was remarkably upregulated by transforming growth factor (TGF)-β1 treatment, and protein expression was prominently increased by additional exposure to TNC. Immunofluorescent labeling demonstrated integrin αvβ6 accumulation in focal adhesions after TNC treatment, especially in combination with TGF-β1. The α2 and β1 subunits were mainly localized at cell-cell contacts, αv being found near cell cluster surfaces. Immunoprecipitation showed increase in αvβ1 heterodimers, but not α2β1, after TNC treatment. Activated β1 subunits detected by an antibody against the Ca(2+)-dependent epitope colocalized with αv in focal adhesion complexes, associated with FAK phosphorylation at tyrosine 925. Neutralizing antibodies against αv and β1 blocked EMT-like change caused by TNC alone. In addition, anti-αv and combined treatment with anti-β1 and anti-αvβ6 inhibited TGF-β1/TNC-induced EMT, whereas either of these alone did not. Integrin subunits αv, β1 and β6, but not α2, bound to TNC immobilized on agarose beads in a divalent cation-dependent manner. Treatments with neutralizing antibodies against β1 and αvβ6 reduced αv subunit bound to the beads. Immunohistochemistry of these receptors in human breast cancer tissues demonstrated frequent expression of β6 subunits in cancer cells forming scattered nests localized in TNC-rich stroma. These findings provide direct evidence that binding of αvβ6 and αvβ1 integrins to TNC as their essential ligand induces EMT-like change in breast cancer cells.
authors: Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, Tsu, Japan.
authors: D
authors: D
authors: Katoh
authors: K
authors: K
authors: Nagaharu
authors: N
authors: N
authors: Shimojo
authors: N
authors: N
authors: Hanamura
authors: M
authors: M
authors: Yamashita
authors: Y
authors: Y
authors: Kozuka
authors: K
authors: K
authors: Imanaka-Yoshida
authors: T
authors: T
authors: Yoshida
references: Clin Cancer Res. 1995 Sep;1(9):1035-41
references: 9816077
references: Int J Cancer. 2003 May 20;105(1):53-60
references: 12672030
references: J Biol Chem. 1990 Apr 15;265(11):5934-7
references: 2138612
references: Clin Oncol (R Coll Radiol). 2008 Feb;20(1):61-6
references: 17981018
references: Virchows Arch. 1999 Nov;435(5):496-500
references: 10592053
references: J Pathol. 2004 Jan;202(1):14-22
references: 14694517
references: J Histochem Cytochem. 2001 Nov;49(11):1341-50
references: 11668187
references: Breast Cancer. 2000 Jan;7(1):19-26
references: 11029766
references: J Cell Commun Signal. 2009 Dec;3(3-4):287-310
references: 19838819
references: Nature. 2008 Jan 10;451(7175):147-52
references: 18185580
references: Exp Cell Res. 2000 Feb 25;255(1):10-7
references: 10666329
references: Cancer Lett. 2006 Dec 8;244(2):143-63
references: 16632194
references: J Biol Chem. 1995 Nov 3;270(44):26232-8
references: 7592829
references: Breast Cancer Res. 2006;8(4):R42
references: 16859511
references: J Invest Dermatol. 1996 Jan;106(1):42-8
references: 8592080
references: Am J Pathol. 2011 Feb;178(2):754-63
references: 21281808
references: Oncogene. 2013 Sep 12;32(37):4406-16
references: 23108397
references: J Neurosci. 1996 Nov 15;16(22):7240-52
references: 8929432
references: J Clin Invest. 2009 Jun;119(6):1438-49
references: 19487820
references: J Cell Sci. 1995 Jun;108 ( Pt 6):2241-51
references: 7673344
references: Clin Exp Metastasis. 2008;25(6):629-42
references: 18461285
references: Nat Cell Biol. 2002 Aug;4(8):632-8
references: 12134161
references: Breast Cancer Res. 2009;11(2):R24
references: 19405959
references: Oncogene. 2013 Jan 10;32(2):141-50
references: 22370635
references: J Oral Pathol Med. 2006 Jan;35(1):1-10
references: 16393247
references: Am J Pathol. 2003 Jun;162(6):1857-67
references: 12759243
references: Anticancer Res. 2009 Jan;29(1):125-30
references: 19331141
references: Curr Drug Targets. 2009 Jul;10(7):645-52
references: 19601768
references: J Cell Sci. 1996 Mar;109 ( Pt 3):643-52
references: 8907709
references: J Cell Sci. 1993 Aug;105 ( Pt 4):1001-12
references: 7693733
references: J Pathol. 2011 Apr;223(5):646-58
references: 21341269
references: Cell. 2009 Nov 25;139(5):871-90
references: 19945376
references: Cell. 1999 Feb 5;96(3):319-28
references: 10025398
references: J Histochem Cytochem. 2000 Jul;48(7):985-98
references: 10858276
references: Int J Cancer. 1997 Jul 17;72(2):369-76
references: 9219848
references: J Clin Invest. 2005 Feb;115(2):339-47
references: 15668738
references: J Oral Pathol Med. 2011 Jan;40(1):46-54
references: 20819124
references: Int J Cancer. 1996 Dec 20;69(6):445-7
references: 8980244
references: J Cell Biol. 2008 Mar 24;180(6):1277-89
references: 18362184
references: Eur J Cell Biol. 2008 Sep;87(8-9):601-15
references: 18342983
references: Eur J Cancer. 1998 Oct;34(11):1687-92
references: 9893653
references: Cell Mol Life Sci. 2011 Oct;68(19):3175-99
references: 21818551
references: Oncogene. 2008 Sep 11;27(40):5373-84
references: 18504437
references: Oral Oncol. 2002 Jun;38(4):332-6
references: 12076695
references: J Pathol. 1997 Aug;182(4):421-8
references: 9306963
references: Br J Cancer. 1998 Dec;78(11):1507-13
references: 9836485
references: J Cell Biol. 1993 Jun;121(5):1141-52
references: 8501119
references: Nat Med. 2011 Jun 26;17(7):867-74
references: 21706029
references: Cancer Sci. 2008 May;99(5):879-87
references: 18294287