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Background  Interleukin-8 (IL-8/CXCL-8) is a prototype of the ELR + CXC chemokines that play an important role in the promotion and progression of many human cancers including breast cancer. We have recently showed the implication of polymorphism (-251) T/A of  IL-8  gene in the susceptibility and prognosis of breast carcinoma. IL-8 acts through its CXCR1 and CXCR2 receptors. CXCR2, expressed on the endothelial cells, is the receptor involved in mediating the angiogenic effects of ELR + CXC chemokines and in particular IL-8.  In the current study, we investigated the susceptibility and prognostic implications of the genetic variation in CXCR2 in breast carcinoma. We also confirmed the implication of  IL-8 (-251) T/A  polymorphism in a larger cohort. Finally, we combined the  IL-8  and  CXCR2  variant alleles and analyzed their effects in breast cancer risk and prognosis.    Methods  We used the allele-specific polymerase chain reaction to characterize the variation of  IL-8  and  CXCR2  for 409 unrelated Tunisian patients with breast carcinoma and 301 healthy control subjects. To estimate the relative risks, Odds ratios and 95% confidence intervals were calculated using unconditional logistic regression after adjusting for the known risk factors for breast cancer. Associations of the genetic marker with the rates of breast carcinoma-specific overall survival and disease-free survival were assessed using univariate and multivariate analyses.    Results  A highly significant association was found between the homozygous  CXCR2  (+ 1208) TT genotype (adjusted OR = 2.89;  P  = 0.008) and breast carcinoma. A significantly increased risk of breast carcinoma was associated with  IL-8  (-251) A allele (adjusted OR = 1.86;  P  = 0.001). The presence of two higher risk genotypes (the TA and TT in  IL-8 , and the TT in  CXCR2 ) significantly increased the risk of developing breast carcinoma (adjusted OR = 4.15;  P  = 0.0004).  The  CXCR2  (+ 1208) T allele manifested a significant association with an aggressive phenotype of breast carcinoma as defined by a large tumor size, a high histological grade, and auxiliary's lymph node metastasis. A significant association between the  IL-8  (-251) A allele and the aggressive form of breast carcinoma was also found.  Moreover, the presence of the  IL-8  (-251) A and/or the  CXCR2  (+ 1208) T allele showed a significant association with a decreased overall survival and disease-free survival in breast carcinoma patients.    Conclusion  Our results indicated that the polymorphisms in  IL-8  and  CXCR2  genes are associated with increased breast cancer risk, as well as disease progress, supporting our hypothesis for IL-8 and ELR + CXC chemokine receptor (CXCR2) involvement in breast cancer pathogenesis.

Combined effects of IL-8 and CXCR2gene polymorphisms on breast cancer susceptibility and aggressiveness