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

Abstract

Integrins are cell surface receptors, which mediate cell-to-cell and cell-to-extracellular matrix adhesion. Some of them, e.g. α_Vβ₃, α_IIbβ₃ 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 α_IIbβ₃ and α_Vβ₃, 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.