Skip to main content

Advertisement

SpringerLink
Log in

Autocrine semaphorin3A stimulates alpha2 beta1 integrin expression/function in breast tumor cells

  • Brief Report
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

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 α2β1 integrin suppress breast tumor cell migration, we studied the impact of SEMA3A signaling on α2β1 integrin expression/function. The incubation of breast tumor cells with SEMA3A increased α2 and β1 integrin levels, and stimulated tumor cell adhesion to the α2β1-binding matrix protein collagen I. Conversely, reducing SEMA3A expression in breast tumor cells decreased α2β1 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 α2β1-neutralizing antibody, we demonstrated that SEMA3A suppression of tumor cell migration is dependent on α2β1. Our studies indicate that expression of the α2β1 integrin, a suppressor of metastatic breast tumor growth, is stimulated in breast tumor cells by an autocrine SEMA3A pathway.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

References

  1. He Z, Tessier-Lavigne M (1997) Neuropilin is a receptor for the axonal chemorepellent semaphorin III. Cell 90(4):739–751. doi:10.1016/S0092-8674(00)80534-6

    Article  CAS  PubMed  Google Scholar 

  2. Kolodkin AL, Levengood DV, Rowe EG, Tai YT, Giger RJ, Ginty DD (1997) Neuropilin is a semaphorin III receptor. Cell 90(4):753–762. doi:10.1016/S0092-8674(00)80535-8

    Article  CAS  PubMed  Google Scholar 

  3. Miao HQ, Soker S, Feiner L, Alonso JL, Raper JA, Klagsbrun M (1999) Neuropilin-1 mediates collapsin-1/semaphorin III inhibition of endothelial cell motility: functional competition of collapsin-1 and vascular endothelial growth factor-165. J Cell Biol 146(1):233–242. doi:10.1083/jcb.146.1.233

    Article  CAS  PubMed  Google Scholar 

  4. Serini G, Valdembri D, Zanivan S, Morterra G, Burkhardt C, Caccavari F et al (2003) Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function. Nature 424(6947):391–397. doi:10.1038/nature01784

    Article  CAS  PubMed  Google Scholar 

  5. Bachelder RE, Lipscomb EA, Lin X, Wendt MA, Chadborn NH, Eickholt BJ et al (2003) Competing autocrine pathways involving alternative neuropilin-1 ligands regulate chemotaxis of carcinoma cells. Cancer Res 63(17):5230–5233

    CAS  PubMed  Google Scholar 

  6. Elices MJ, Hemler ME (1989) The human integrin VLA-2 is a collagen receptor on some cells and a collagen/laminin receptor on others. Proc Natl Acad Sci USA 86(24):9906–9910. doi:10.1073/pnas.86.24.9906

    Article  CAS  PubMed  Google Scholar 

  7. Chen J, Diacovo TG, Grenache DG, Santoro SA, Zutter MM (2002) The alpha(2) integrin subunit-deficient mouse: a multifaceted phenotype including defects of branching morphogenesis and hemostasis. Am J Pathol 161(1):337–344

    CAS  PubMed  Google Scholar 

  8. Faraldo MM, Deugnier MA, Lukashev M, Thiery JP, Glukhova MA (1998) Perturbation of beta1-integrin function alters the development of murine mammary gland. EMBO J 17(8):2139–2147. doi:10.1093/emboj/17.8.2139

    Article  CAS  PubMed  Google Scholar 

  9. Naylor MJ, Li N, Cheung J, Lowe ET, Lambert E, Marlow R et al (2005) Ablation of beta1 integrin in mammary epithelium reveals a key role for integrin in glandular morphogenesis and differentiation. J Cell Biol 171(4):717–728. doi:10.1083/jcb.200503144

    Article  CAS  PubMed  Google Scholar 

  10. Maschler S, Wirl G, Spring H, Bredow DV, Sordat I, Beug H et al (2005) Tumor cell invasiveness correlates with changes in integrin expression and localization. Oncogene 24(12):2032–2041. doi:10.1038/sj.onc.1208423

    Article  CAS  PubMed  Google Scholar 

  11. Zutter MM, Krigman HR, Santoro SA (1993) Altered integrin expression in adenocarcinoma of the breast. Analysis by in situ hybridization. Am J Pathol 142(5):1439–1448

    CAS  PubMed  Google Scholar 

  12. Zutter MM, Mazoujian G, Santoro SA (1990) Decreased expression of integrin adhesive protein receptors in adenocarcinoma of the breast. Am J Pathol 137(4):863–870

    CAS  PubMed  Google Scholar 

  13. Gui GP, Puddefoot JR, Vinson GP, Wells CA, Carpenter R (1995) In vitro regulation of human breast cancer cell adhesion and invasion via integrin receptors to the extracellular matrix. Br J Surg 82(9):1192–1196. doi:10.1002/bjs.1800820914

    Article  CAS  PubMed  Google Scholar 

  14. Lochter A, Navre M, Werb Z, Bissell MJ (1999) Alpha1 and alpha2 integrins mediate invasive activity of mouse mammary carcinoma cells through regulation of stromelysin-1 expression. Mol Biol Cell 10(2):271–282

    CAS  PubMed  Google Scholar 

  15. Keely PJ, Fong AM, Zutter MM, Santoro SA (1995) Alteration of collagen-dependent adhesion, motility, and morphogenesis by the expression of antisense alpha 2 integrin mRNA in mammary cells. J Cell Sci 108(Pt 2):595–607

    CAS  PubMed  Google Scholar 

  16. Zutter MM, Santoro SA, Staatz WD, Tsung YL (1995) Re-expression of the alpha 2 beta 1 integrin abrogates the malignant phenotype of breast carcinoma cells. Proc Natl Acad Sci USA 92(16):7411–7415. doi:10.1073/pnas.92.16.7411

    Article  CAS  PubMed  Google Scholar 

  17. Eickholt BJ, Walsh FS, Doherty P (2002) An inactive pool of GSK-3 at the leading edge of growth cones is implicated in semaphorin 3A signaling. J Cell Biol 157(2):211–217. doi:10.1083/jcb.200201098

    Article  CAS  PubMed  Google Scholar 

  18. Coghlan MP, Culbert AA, Cross DA, Corcoran SL, Yates JW, Pearce NJ et al (2000) Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription. Chem Biol 7(10):793–803. doi:10.1016/S1074-5521(00)00025-9

    Article  CAS  PubMed  Google Scholar 

  19. Roberts MS, Woods AJ, Dale TC, Van Der Sluijs P, Norman JC (2004) Protein kinase B/Akt acts via glycogen synthase kinase 3 to regulate recycling of alpha v beta 3 and alpha 5 beta 1 integrins. Mol Cell Biol 24(4):1505–1515. doi:10.1128/MCB.24.4.1505-1515.2004

    Article  CAS  PubMed  Google Scholar 

  20. DiMilla PA, Stone JA, Quinn JA, Albelda SM, Lauffenburger DA (1993) Maximal migration of human smooth muscle cells on fibronectin and type IV collagen occurs at an intermediate attachment strength. J Cell Biol 122(3):729–737. doi:10.1083/jcb.122.3.729

    Article  CAS  PubMed  Google Scholar 

  21. Lynch L, Vodyanik PI, Boettiger D, Guvakova MA (2005) Insulin-like growth factor I controls adhesion strength mediated by alpha5 beta1 integrins in motile carcinoma cells. Mol Biol Cell 16(1):51–63. doi:10.1091/mbc.E04-05-0399

    Article  CAS  PubMed  Google Scholar 

  22. Murga M, Fernandez-Capetillo O, Tosato G (2005) Neuropilin-1 regulates attachment in human endothelial cells independently of vascular endothelial growth factor receptor-2. Blood 105(5):1992–1999. doi:10.1182/blood-2004-07-2598

    Article  CAS  PubMed  Google Scholar 

  23. Kashiwagi H, Shiraga M, Kato H, Kamae T, Yamamoto N, Tadokoro S et al (2005) Negative regulation of platelet function by a secreted cell repulsive protein, semaphorin 3A. Blood 106(3):913–921. doi:10.1182/blood-2004-10-4092

    Article  CAS  PubMed  Google Scholar 

  24. Lepelletier Y, Smaniotto S, Hadj-Slimane R, Villa-Verde DM, Nogueira AC, Dardenne M et al (2007) Control of human thymocyte migration by neuropilin-1/semaphorin-3A-mediated interactions. Proc Natl Acad Sci USA 104(13):5545–5550. doi:10.1073/pnas.0700705104

    Article  CAS  PubMed  Google Scholar 

  25. Herman JG, Meadows GG (2007) Increased class 3 semaphorin expression modulates the invasive and adhesive properties of prostate cancer cells. Int J Oncol 30(5):1231–1238

    CAS  PubMed  Google Scholar 

  26. Castellani V, Chedotal A, Schachner M, Faivre-Sarrailh C, Rougon G (2000) Analysis of the L1-deficient mouse phenotype reveals cross-talk between Sema3A and L1 signaling pathways in axonal guidance. Neuron 27(2):237–249. doi:10.1016/S0896-6273(00)00033-7

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Ken Young for his assistance with these studies. This work was supported by Department of Defense Breast Cancer Research Program Concept Award W81XAH-07-1-0639 (R.E.B.), as well as by NIH grant CA093855(R.E.B.).

Author information

Authors and Affiliations

  1. Department of Pathology, Duke University Medical Center, P.O. Box 3712 D.U.M.C., Durham, NC, 27710, USA

    Hongjie Pan, Luke S. Wanami, Thusitha R. Dissanayake & Robin E. Bachelder

Authors
  1. Hongjie Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luke S. Wanami
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thusitha R. Dissanayake
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Robin E. Bachelder
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robin E. Bachelder.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pan, H., Wanami, L.S., Dissanayake, T.R. et al. Autocrine semaphorin3A stimulates alpha2 beta1 integrin expression/function in breast tumor cells. Breast Cancer Res Treat 118, 197–205 (2009). https://doi.org/10.1007/s10549-008-0179-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-008-0179-y

Keywords

Search

Navigation