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

Abstract

BackgroundInterleukin-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.MethodsWe 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.ResultsA 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.ConclusionOur 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.

Distribution of CXCR2 +1208 T/C gene polymorphisms in relation to opportunistic infections among HIV-infected patients in Limpopo Province, South Africa

“…The CXCR2 TC genotype was found to be more abundant, suggesting that patients in the Limpopo Province primarily carry the heterozygous TC genotype compared to other homozygous genotypes. However, different results obtained by Snoussi et al (2010) suggested that the CC genotype was the predominant genotype among the Tunisian population. These authors also found a highly significant association between the homozygous CXCR2 (+ 1208) TT genotype and breast carcinoma in terms of frequency, but also found a significant association with an aggressive phenotype of breast carcinoma as defined by large tumor size, high histological grade, and auxiliary lymph node metastasis (Snoussi et al, 2010).…”

“…CXCR2 and its chemokine ligands genotypes are involved in a wide range of acute and chronic inflammatory diseases, including acute respiratory distress syndrome (Kurdowska et al, 2002), rheumatoid arthritis (Erdem et al, 2005;Lally et al, 2005), psoriasis (Reich et al, 2001), inflammatory bowel disease (Banks et al, 2003), chronic obstructive pulmonary disease and asthma (Keatings et al, 1996;Beeh et al, 2003;Chapman et al, 2009), aggressive cancer (Snoussi et al, 2010), cystic fibrosis (Koller et al, 1997), and atherosclerosis (Bizzarri et al, 2006). However, whether different genotypes of the genes coding for these cytokines are involved in the susceptibility to opportunistic infections among HIV patients is not clear.…”

“…A 20-µL PCR mixture was prepared and contained 5 µL genomic DNA, 10 µL Kappa ready mix Taq polymerase (KAPPA Biotechnologies; Cape Town, South Africa), 0.3 µL each specific and common primer, and nuclease-free water. The primers used were CXCR2 (+1208) common (5ꞌ-GTCTTGTGAATAAGCTGCTATGA-3ꞌ), CXCR2 (+1208) C allele (5ꞌ-CCATTGTGGTCACAGGAAGC-3ꞌ), and CXCR2 (+1208) T allele (5ꞌ-CCATTGTGGTCACAGGAAGT-3ꞌ), yielding a PCR product of approximately 700-720 base pairs (bp) as described by Snoussi et al (2010).…”

Association of interleukin-8 gene polymorphisms in HIV patients with opportunistic infections in Limpopo Province, South Africa

“…The primers used were 5'-CTAGAAATAAAAAAGCATACAA-3'; (-251A) 5'-CTAGAAATAAAAAAGCATACAT-3' (-251T); and the common primer 5'-AATACGGAGT ATGACGAAA-3'. These primers yielded a PCR product of about 200 bp, as described by Snoussi et al (2010). AS-PCR cycling conditions were as follows: predenaturation at 96°C for 10 min, a touchdown procedure of 25 s at 95°C followed by annealing for 45 s at temperatures decreasing from 55°C (four cycles) to 50°C (25 cycles), and elongation at 72°C for 40 s. PCR products were stored at 10°C.…”

“…Biomedical and genetic studies have shown the effects of IL-8 gene polymorphisms in the pathogenesis of chronic inflammatory diseases, such as cancer (Snoussi et al, 2010), tuberculosis (TB) (Otsuka et al, 2005), and other infections. Nevertheless, no studies have investigated the effects of IL-8 on OIs in HIV patients.…”