Association of Breast Cancer and Polymorphisms of Interleukin-10 and Tumor Necrosis Factor-α Genes

Abstract

We investigated the potential relationship between breast cancer and polymorphisms of the interleukin 10 (IL-10) and tumor necrosis factor-α (TNF-α) genes. High plasma TNF-α concentrations predict poor cancer outcome (1), weight loss, cachexia, poor immune response, and anemia (2)(3). We studied the −308(G/A) polymorphism because it is the most frequently investigated, it is included in an AP-2 transcription-factor binding site of the TNF-α gene (4)(5)(6), and its importance in TNF-α gene expression has been demonstrated by reporter gene assays (7). The TNF-α −308 polymorphism affects TNF-α gene transcription in both a cell-type and stimulus-specific manner, with a remarkable effect in macrophage-like cells (8). IL-10, an important immunoregulatory cytokine, induces T-cell anergy (9) and prevents tumor antigen presentation to CD8+ cytotoxic T lymphocytes by suppressing expression of MHC class I and II antigens (10). This effect may contribute to the lack of immune response toward transformed cells (11)(12)(13). Three polymorphisms [−1082(G/A), −819(C/T), and −592(C/A)] have been described in the IL-10 promoter region, but data are unclear regarding their influence, alone or in reciprocal linkage, on transcription (14). Higher IL-10 production seems to be associated with −1082 G/G. The positive effect on IL-10 gene expression was substantiated by reporter gene assays (15)(16), although, in some cases, differing results have been described in cells undergoing distinct stimuli (17). There appears to be conflicting evidence on the interplay between IL-10 and cancer. Indeed, it has been proposed that IL-10 might contribute to tumor escape from the immune response, but it may also exert an antitumor effect. In one study, IL-10-deficient mice developed colitis and colorectal cancer, mirroring the increased colorectal cancer incidence observed in patients with inflammatory bowel disease (18). In another study, the results indicated that the G/G genotype, …