Breast Cancer Research and Treatment

, Volume 97, Issue 1, pp 67–72 | Cite as

Integrin alpha-2 and beta-3 gene polymorphisms and breast cancer risk

  • Uwe LangsenlehnerEmail author
  • Wilfried Renner
  • Babak Yazdani-Biuki
  • Tanja Eder
  • Thomas C. Wascher
  • Bernhard Paulweber
  • Heimo Clar
  • Günter Hofmann
  • Hellmut Samonigg
  • Peter Krippl


Integrins are cell surface receptors, which mediate cell-to-cell and cell-to-extracellular matrix adhesion. Some of them, e.g. αVβ3, αIIbβ3 and α2β1, have been suggested as key players for cancer development and tumor metastasis. Two polymorphisms in the gene for the α2 component, ITGA2 807C>T and 1648G>A, have been associated with the cell-surface density of integrin α2β1. The 176T>C polymorphism in the ITGB3 gene, encoding the β3 subunit of integrins αIIbβ3 and αVβ3, modifies a variety of traits of β3 expressing cells. To analyze the role of ITGA2 and ITGB3 polymorphisms for breast cancer risk and prognosis, we performed a case-control study including 500 female breast cancer patients and 500 healthy female age-matched control subjects. All study participants were of Caucasian origin (Austria, Middle-Europe). The ITGA2 1648_AA genotype was significantly associated with breast cancer (odds ratio 3.12; 95% confidence interval 1.11–8.77). Carriers of the most common ITGA2 haplotype (807C_1648G, ‘wildtype’) were at decreased risk for breast cancer (odds ratio 0.72; 95% confidence interval 0.53–0.98). A histological grade of 3 or 4 was found more often in ITGA2 807TT subjects (p=0.039 compared to CC+CT genotypes) and carriers of an ITGA2 1648A allele (p=0.017 compared to GG genotype). Carriers of the ITGA2 807C_1648G haplotype were less likely to have a histological grade 3 or 4 compared to non-carriers (p=0.003). The ITGB3 176T>C polymorphisms was not associated with breast cancer susceptibility. In a Cox-regression analysis, carriers of the homozygous ITGB3 176-CC genotype had a higher risk for metastasis (relative risk 2.3; 95% CI 1.3–4.2; p=0.005). We conclude that functional polymorphisms in integrin genes ITGA2 and ITGB3 influence the development and progression of breast cancer, respectively. The precise mechanism remains to be determined, but likely involves dysregulated signaling pathways.


breast cancer epidemiology genetics integrin, glykoprotein 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.



This study was supported by the Austrian Cancer Aid/Styria (Project-Nr. 02/2004) and the Hans-und-Blanca-Moser foundation.


  1. 1.
    Parise LV, Lee J, Juliano RL, New aspects of integrin signaling in cancerSemin Cancer Biol2000;10:407–414CrossRefPubMedGoogle Scholar
  2. 2.
    Nierodzik ML, Klepfish A, Kaspatkin S, Role of the platelets, thrombin, integrin IIb–IIIa, fibronectin and von Willebrand Factor on tumor adhesion in vitro and metastasis in vivoThromb Haemost 1995;74:282–290PubMedGoogle Scholar
  3. 3.
    Gui GPH, Puddefoot JR, Vinson GP, Wells CA, Carpenter R, Altered cell–matrix contact: a prerequisite for breast cancer metastasis?Br J Cancer 1997;75:623–633PubMedGoogle Scholar
  4. 4.
    Felding-Habermann B, O’Toole TE, Smith JW, Fransvea E, Ruggeri ZM, Ginsberg MH, et al. Integrin activation controls metastasis in human breast cancerProc Natl Acad Sci USA 2001;98:1853–1858CrossRefPubMedGoogle Scholar
  5. 5.
    Hood JD, Cheresh DA, Role of integrins in cell invasion and migration Nat Rev Cancer 2002;2:91–100CrossRefPubMedGoogle Scholar
  6. 6.
    Varner JA, Cheresh DA: Tumor angiogenesis and the role of vascular cell integrin alphavbeta3. Important Adv Oncol 69–87, 1996Google Scholar
  7. 7.
    Kritzik M, Savage B, Nugent DJ, Santoso S, Ruggeri ZM, Kunicki TJ Nucleotide polymorphisms in the α2 gene define multiple alleles that are associated with differences in platelet α2β1 densityBlood 1998;92:2382–2388PubMedGoogle Scholar
  8. 8.
    Corral J, Rivera J, González-Conejero R, Vicente V, The platelet GP Ia receptor density associates with the genetically linked 807 C/T and HPA-5 polymorphisms Transfusion 1999;39:372–378CrossRefPubMedGoogle Scholar
  9. 9.
    Bennett JS, Catella-Lawson F, Rut AR, Vilaire G, Qi W, Kapoor SC, Murphy S, FitzGerald GA, Effect of the Pl(A2) alloantigen on the function of beta(3)-integrins in plateletsBlood 2001;97:3093–3099CrossRefPubMedGoogle Scholar
  10. 10.
    Vijayan KV, Liu Y, Dong JF, Bray PF, Enhanced activation of mitogenactivated protein kinase and myosin light chain kinase by the Pro33 polymorphism of integrin beta 3J Biol Chem 2003;278:3860–3867CrossRefPubMedGoogle Scholar
  11. 11.
    Feng D, Lindpaintner K, Larson MG, Rao VS, O’Donnell CJ, Lipinska I, Schmitz C, Sutherland PA, Silbershatz H, D’Agostino RB, Muller JE, Myers RH, Levy D, Tofler GH, Increased platelet aggregability associated with platelet GPIIIa PlA2 polymorphism: the Framingham Offspring StudyArterioscler Thromb Vasc Biol 1999;19:1142–1147PubMedGoogle Scholar
  12. 12.
    Krippl P, Langsenlehner U, Renner W, Yazdani-Biuki B, Wolf G, Wascher TC, Paulweber B, Haas J, Samonigg H, A common 936 C/T gene polymorphism of vascular endothelial growth factor is associated with decreased breast cancer riskInt J Cancer 2003;106:468–471CrossRefPubMedGoogle Scholar
  13. 13.
    Langsenlehner U, Krippl P, Renner W, Yazdani-Biuki B, Wolf G, Wascher TC, Paulweber B, Weitzer W, Samonigg H, The common 677C>T gene polymorphism of methylenetetrahydrofolate reductase gene is not associated with breast cancer riskBreast Cancer Res Treat 2003; 81:169–172CrossRefPubMedGoogle Scholar
  14. 14.
    Krippl P, Langsenlehner U, Renner W, Yazdani-Biuki B, Wolf G, Wascher TC, Paulweber B, Köppel H, Samonigg H, The 5A/6A polymorphism of the matrix metalloproteinase 3 gene promotor and breast cancerClin Cancer Res 2004;10:3518–3520CrossRefPubMedGoogle Scholar
  15. 15.
    Krippl P, Langsenlehner U, Renner W, Yazdani-Biuki B, Wolf G, Wascher TC, Paulweber B, Weitzer W, Leithner A, Samonigg H, The 870G>A polymorphism of the Cyclin D1 gene is not associated with breast cancerBreast Cancer Res Treat 2003;82:165–168CrossRefPubMedGoogle Scholar
  16. 16.
    Esterbauer H, Schneitler C, Oberkofler H, Ebenbichler C, Paulweber B, Sandhofer F, Ladurner G, Hell E, Strosberg AD, Patsch JR, Krempler F, Patsch W, A common polymorphism in the promoter of UCP2 is associated with decreased risk of obesity in middle-aged humansNat Genet 2001;28:178–183CrossRefPubMedGoogle Scholar
  17. 17.
    Stephens M, Smith NJ, Donnelly P, A new statistical method for haplotype reconstruction from population dataAm J Hum Genet 2001;68:978–989CrossRefPubMedGoogle Scholar
  18. 18.
    Zutter MM, Mazoujian G, Santoro SA, Decreased expression of integrin adhesive protein receptors in adenocarcinoma of the breast Am J Pathol 1990;137:863–870PubMedGoogle Scholar
  19. 19.
    Zutter MM, Santoro SA, Staatz WD, Tsung YL, Re-expression of the alpha 2 beta 1 integrin abrogates the malignant phenotype of breast carcinoma cellsProc Natl Acad Sci USA 1995;92:7411–7415CrossRefPubMedGoogle Scholar
  20. 20.
    Ayala F, Corral J, Gonzalez-Conejero R, Sanchez I, Moraleda JM, Vicente V, Genetic polymorphisms of platelet adhesive molecules: association with breast cancer risk and clinical presentationBreast Cancer Res Treat 2003;80:145–154CrossRefPubMedGoogle Scholar
  21. 21.
    Wang-Gohrke S, Chang-Claude J, Integrin beta3 Leu33Pro polymorphism and breast cancer risk: a population-based case-control study in GermanyBreast Cancer Res Treat 2004;88:231–237CrossRefPubMedGoogle Scholar
  22. 22.
    Bojesen SE, Tybjaerg-Hansen A, Nordestgaard BG, Integrin beta3 Leu33Pro homozygosity and risk of cancerJ Natl Cancer Inst 2003;95:1150–1157PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2005

Authors and Affiliations

  • Uwe Langsenlehner
    • 1
    • 7
    Email author
  • Wilfried Renner
    • 2
  • Babak Yazdani-Biuki
    • 3
  • Tanja Eder
    • 4
  • Thomas C. Wascher
    • 3
  • Bernhard Paulweber
    • 5
  • Heimo Clar
    • 6
  • Günter Hofmann
    • 1
  • Hellmut Samonigg
    • 1
  • Peter Krippl
    • 1
  1. 1.Department of Internal Medicine, Division of OncologyMedical University GrazGrazAustria
  2. 2.Clinical Institute of Medical and Laboratory DiagnosticsMedical University GrazGrazAustria
  3. 3.Department of Internal MedicineMedical University GrazGrazAustria
  4. 4.Department of RadiooncologyMedical University GrazGrazAustria
  5. 5.Department of Internal MedicineMedical University SalzburgSalzburgAustria
  6. 6.Department of OrthopaedicsMedical University GrazGrazAustria
  7. 7.Department of Internal Medicine, Division of OncologyMedical University GrazGrazAustria

Personalised recommendations