The −174 G/C gene polymorphism in interleukin-6 is associated with an aggressive breast cancer phenotype

Abstract

Serum and tissue levels of interleukin-6 (IL-6) have been implicated in the biological phenotype of breast carcinoma. A common G/C polymorphism at position À174 of the IL-6 promoter can influence the expression level of this gene. We therefore investigated for associations between this polymorphism and various phenotypic features in a series of 256 breast cancers. Individuals who were homozygous for the C allele (n ¼ 55) were more likely to have higher-grade tumours (P ¼ 0.039) with ductal histology (P ¼ 0.030) compared to those harbouring at least one wild-type G allele (n ¼ 201). Homozygosity for the C allele was also associated with significantly worse overall survival (P ¼ 0.031). We conclude that the À174 C allele of IL-6 is associated with a more aggressive breast cancer phenotype. Interleukin-6 (IL-6) is a pleiotropic growth factor involved in many physiological and pathological processes including carcinogenesis (Ishihara and Hirano, 2002). High serum levels of IL-6 have been associated with advanced stage disease and worse prognosis for several cancer types including ovarian, breast and colorectal (Berek et al, 1991;Zhang and Adachi, 1999;Belluco et al, 2000;Bachelot et al, 2003). In contrast, however, high levels of IL-6 protein and mRNA expression within the breast carcinoma tissue have been linked to better prognosis and to a less malignant phenotype (Basolo et al, 1996;Fontanini et al, 1999;Karczewska et al, 2000).A common G/C polymorphism located within the IL-6 promoter at position À174 has been reported to influence IL-6 expression, with the G allele being associated with higher expression levels (Fishman et al, 1998;Terry et al, 2000;Vickers et al, 2002). This polymorphism has been implicated in a number of chronic disease conditions including arthritis, coronary heart disease and diabetes (Fishman et al, 1998;Fernandez-Real et al, 2000;Yudkin et al, 2000). In human cancer, the À174 G/C IL-6 polymorphism does not appear to be a risk factor for the development of multiple myeloma or melanoma (Zheng et al, 2000;Martinez-Escribano et al, 2002). Recent data, however, suggest that the C allele is associated with an increased risk of colorectal cancer (Landi et al, 2003). Furthermore, in ovarian cancer, the C allele is associated with an earlier stage of disease and with significantly better survival (Hefler et al, 2003). In light of the earlier studies linking serum and tissue IL-6 levels to breast cancer outcomes, the aim of the present study was to investigate for possible associations between the À174 G/C IL-6 polymorphism and phenotypic characteristics of breast cancer. MATERIALS AND METHODS Breast cancersConsecutive cases of breast cancer treated surgically between 1992 and 1993 at the Sir Charles Gairdner or Royal Perth Hospitals in Perth, Australia, were selected for study. Genomic DNA was extracted from surgical specimens using standard techniques. The median age of patients at surgery was 59 years (range 18 -93 years) and the median follow-up time was 57 months (range 2 -96 months). Clinical...

Interleukin-1 and Interleukin-6 Gene Polymorphisms and the Risk of Breast Cancer in Caucasian Women

“…As previously published for other malignancies (29), the À174 G/C IL6 polymorphism likely is important for carcinogenesis. Previously published data are conflicting (34,35). We cannot confirm data on the association between the IL6 polymorphism and clinicopathologic variables.…”

“…DeMichele et al reported that the presence of the IL6 polymorphism was associated with an improved outcome in high-risk breast cancer (33), whereas Iacopetta et al showed that the IL6 polymorphism was predictive of an aggressive breast cancer phenotype (34).…”

IL6, Aspirin, Nonsteroidal Anti-inflammatory Drugs, and Breast Cancer Risk in Women Living in the Southwestern United States

“…Gonzalez-Zuloeta et al (35) reported a nonsignificant 24% increased risk of breast cancer with IL6 in a nested case-control analysis in the Rotterdam Study. Two studies that have reported associations with survival after diagnosis with breast cancer have contradictory results with regard to the direction of effect of the C allele (36,37). Unfortunately, little is known about functionality of haplotypes, and we can only hypothesize that the function of the haplotype that includes multiple SNPs is similar in action to the functional SNPs within it.…”

Interleukin‐6 and its receptor in cancer

“…Singlenucleotide polymorphisms in the IL-6 promoter, particularly the 2174 G/C polymorphism, have been associated with an aggressive breast cancer phenotype 47 and with breast cancer susceptibility and prognosis. 48 For example, inflammatory breast cancer has a higher metastatic potential than noninflammatory breast cancer.…”