title: Autocrine semaphorin3A stimulates alpha2 beta1 integrin expression/function in breast tumor cells.
abstract: The axon repulsion factor semaphorin3A (SEMA3A) and its receptor neuropilin-1 (NP-1) are expressed in breast tumor cells, and function as suppressors of tumor cell migration. Based on the knowledge that both SEMA3A and the alpha2beta1 integrin suppress breast tumor cell migration, we studied the impact of SEMA3A signaling on alpha2beta1 integrin expression/function. The incubation of breast tumor cells with SEMA3A increased alpha2 and beta1 integrin levels, and stimulated tumor cell adhesion to the alpha2beta1-binding matrix protein collagen I. Conversely, reducing SEMA3A expression in breast tumor cells decreased alpha2beta1 levels and collagen adhesion. The ability of SEMA3A to increase tumor cell adhesion to collagen was dependent on both the SEMA3A receptor NP-1 and the glycogen synthase kinase-3. The incubation of breast tumor cells with SEMA3A disrupted the actin cytoskeleton, and reduced both tumor cell migratory and invasive behavior. Importantly, using an alpha2beta1-neutralizing antibody, we demonstrated that SEMA3A suppression of tumor cell migration is dependent on alpha2beta1. Our studies indicate that expression of the alpha2beta1 integrin, a suppressor of metastatic breast tumor growth, is stimulated in breast tumor cells by an autocrine SEMA3A pathway.
authors.affiliation: Department of Pathology, Duke University Medical Center, P.O. Box 3712 D.U.M.C., Durham, NC, 27710, USA.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Pan
authors.forename: Luke S
authors.initials: LS
authors.lastname: Wanami
authors.forename: Thusitha R
authors.initials: TR
authors.lastname: Dissanayake
authors.forename: Robin E
authors.initials: RE
authors.lastname: Bachelder
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D019898:Autocrine Communication / Q000502:physiology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion; D045744:Cell Line, Tumor / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement; D024042:Collagen Type I; D003599:Cytoskeleton / Q000648:ultrastructure; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D038982:Integrin alpha2beta1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D039942:Neuropilin-1 / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D040121:Semaphorin-3A / Q000494:pharmacology / Q000502:physiology*
chemical_list: D057134:Antibodies, Neutralizing; D024042:Collagen Type I; D038982:Integrin alpha2beta1; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; C108639:SEMA3A protein, human; D040121:Semaphorin-3A; D039942:Neuropilin-1
references.citation: Oncogene. 2005 Mar 17;24(12):2032-41
references.pmid: 15688013
references.citation: J Cell Biol. 2002 Apr 15;157(2):211-7
references.pmid: 11956225
references.citation: Cell. 1997 Aug 22;90(4):739-51
references.pmid: 9288753
references.citation: Am J Pathol. 1993 May;142(5):1439-48
references.pmid: 8388172
references.citation: Blood. 2005 Mar 1;105(5):1992-9
references.pmid: 15522955
references.citation: Br J Surg. 1995 Sep;82(9):1192-6
references.pmid: 7551993
references.citation: Am J Pathol. 2002 Jul;161(1):337-44
references.pmid: 12107118
references.citation: J Cell Sci. 1995 Feb;108 ( Pt 2):595-607
references.pmid: 7769004
references.citation: Cancer Res. 2003 Sep 1;63(17):5230-3
references.pmid: 14500350
references.citation: J Cell Biol. 1993 Aug;122(3):729-37
references.pmid: 8335696
references.citation: Neuron. 2000 Aug;27(2):237-49
references.pmid: 10985345
references.citation: Mol Biol Cell. 1999 Feb;10(2):271-82
references.pmid: 9950676
references.citation: J Cell Biol. 2005 Nov 21;171(4):717-28
references.pmid: 16301336
references.citation: Mol Cell Biol. 2004 Feb;24(4):1505-15
references.pmid: 14749368
references.citation: Nature. 2003 Jul 24;424(6947):391-7
references.pmid: 12879061
references.citation: Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7411-5
references.pmid: 7638207
references.citation: Mol Biol Cell. 2005 Jan;16(1):51-63
references.pmid: 15509657
references.citation: EMBO J. 1998 Apr 15;17(8):2139-47
references.pmid: 9545227
references.citation: Cell. 1997 Aug 22;90(4):753-62
references.pmid: 9288754
references.citation: J Cell Biol. 1999 Jul 12;146(1):233-42
references.pmid: 10402473
references.citation: Proc Natl Acad Sci U S A. 2007 Mar 27;104(13):5545-50
references.pmid: 17369353
references.citation: Chem Biol. 2000 Oct;7(10):793-803
references.pmid: 11033082
references.citation: Int J Oncol. 2007 May;30(5):1231-8
references.pmid: 17390026
references.citation: Am J Pathol. 1990 Oct;137(4):863-70
references.pmid: 2221016
references.citation: Blood. 2005 Aug 1;106(3):913-21
references.pmid: 15831706
references.citation: Proc Natl Acad Sci U S A. 1989 Dec;86(24):9906-10
references.pmid: 2557634