Introduction
Breast cancer is the most common malignancy threatening the health and life of women and it's incidence has increased in recent years in both developed and developing countries[
1]. Biologic mechanisms leading to the development of breast cancer are not clearly understood, but the role of cytokines in cancer immunity and carcinogenesis has been well established[
2]. As a multifunctional Th2-cytokine with both immunosuppressive and anti-angiogenic functions, interleukin-10 (IL-10) may have both tumor-promoting and tumor-inhibiting properties[
3]. Recent data suggest that polymorphic variations in the promoter sequences of IL-10 gene may influence the gene expression[
4,
5] and consequently play a certain role in susceptibility and clinical course of breast cancer.
IL-10 is an important immunoregulatory cytokine mainly produced by activated T cells, monocytes, B cells and thymocytes. As an immune response modulator, IL-10 can both stimulate and suppress the immune response[
6]. Numerous studies have shown that IL-10 may be involved in the pathogenesis of cancer, but the results were inconsistent. On the one hand, increased serum IL-10 levels could facilitate development of cancer by suppressing expression of MHC class I and II antigens[
7] and preventting tumor antigen presentation to CD8-cytotoxic T lymphocytes. On the other hand, anti-angiogenic effects of IL-10 are supposed to play a protective and preventive role against tumor.
The gene encoding IL-10 is located on human chromosome 1q31-1q32[
8,
9], and is composed of five exons and four introns. It has been reported that several important polymorphic sites in the IL-10 gene, including three in the promoter region (-1082 (A/G, -819 T/C, -592 A/C) may influence the transcription of IL-10 messenger RNA and the expression of IL-10 in vitro [
10‐
12]. Although several studies have shown the possible involvement of IL-10 in the pathogenesis of breast cancer, as well as its association with prognosis in different ethnic populations, the results were not all consistent[
13]. Furthermore, little is known about the effect of these polymorphisms on the risk of beast cancer in the Han Chinese population. The goal of this study was to evaluate whether IL-10 gene promoter -1082A/G, -819T/C and -592A/C polymorphisms and haplotypes were associated with breast cancer in a Han Chinese population.
Discussion
In this case-control study we evaluated the association between the polymorphisms of the IL-10 promoter and breast cancer in a Han Chinese population. Our data did not show significant differences in allele, genotype and haplotype frequencies between breast cancer patients and healthy controls. In concordance with our study, Howell et al.[
16], Smith et al. [
17] and Balasubramanian et al.[
18] reported that there were no apparent relationship of the IL-10 gene promoter polymorphisms with the risk of breast cancer. However, these results are not consistent with the study conducted in Austrian previously, in which the -592AA genotype was shown to be associated with a reduced breast cancer risk[
19]. Moreover, another study from the Italian population showed that the IL-10 -1082AA genotype was correlated with a marked increase in breast cancer risk[
20]. Although it is difficult to determine the reasons behind the contradictory results in these studies, the different genetic background of study population may be one of the main factors.
In this study, we found that the frequencies of the -1082 G, -819 C and -592 C alleles among the healthy controls (0.061, 0.380 and 0.380, respectively) were similar to those observed in an Asian population[
21,
22] but significantly lower than those of European Caucasians [
23‐
25]. We also found that there was strong linkage disequilibrium among the -1082A/G, -819 T/C and -592 A/C polymorphisms. Complete linkage disequilibrium was observed between locus -819T/C and locus -592 A/C. Four possible haplotypes were demonstrated in our population. Major haplotype frequency of the ATA among the controls in the present study was 0.585, which was significantly higher than those of study performed in the European Caucasians (0.290 and 0.248, respectively)[
24,
26]. These results suggest that the frequencies of IL-10 gene alleles and haplotypes might vary among the different ethnic population.
Although we did not find an association of the IL-10 gene polymorphisms with risk of breast cancer, in present study we reported for the first time that the IL-10 promoter haplotypes and -1082 A/G polymorphism were significantly associated with the prognostic and predictive factors of breast cancer in Chinese han women. Our data showed that the -1082AA genotype was associated with a significantly increased risk of lymph node (LN) involvement (P = 0.041) and larger tumor size (P = 0.039) at the time of diagnosis. Moreover, in the haplotype analysis of IL-10 gene, we also found that patients carrying ATA haplotype were in higher LN involvement (p = 0.022) and higher tumor stage(p = 0.028) of breast cancer at the time of diagnosis compared with others. The findings suggest that the IL-10 ATA haplotype and -1082AA genotype might be adverse prognostic factors in breast cancer in Chinese Han women.
IL-10 is a multifunctional cytokine with both immunosuppressive and antiangiogenic functions, which may play varied roles in the pathogenesis and development of breast cancer. Although the genetic control of IL-10 expression is not clearly understood yet, polymorphisms in promoter have been reported to determine interindividual differences in IL-10 production[
4,
9]. Previous studies indicated that IL-10 promoter -1082 AA genotype was associated with decreased IL-10 expression[
27]. ATA haplotype formed by polymorphisms at positions -1,082, -819 and -592 in the promoter of the IL-10 gene has been is generally assumed to be a lower IL-10 responder[
10‐
12]. This and the present study indicate that low levels of IL-10 may play a facilitative role in the development of breast cancer. Findings of our study are further supported by a recent study showing that the low-expression allele and haplotype were associated with reduced disease-free survival and the IL-10 gene polymorphisms may be a potential prognosis marker in breast cancer for disease-free survival[
28]. The mechanism for this remains unclear, but may likely include anti-angiogenic functions of IL-10.
In conclusion, in this case-control study, we report for the first time that the IL-10 promoter polymorphisms were significantly associated with the prognostic and predictive factors of breast cancer in a Chinese han population. The main finding of our study suggests that IL-10 promoter polymorphisms participate in the progression of breast cancer rather than in its initial development. Considering limited sample size, nonrandom sampling and pitfalls of unknown confounders, further studies with larger sample size from different ethnic origins are required to confirm and extend our observations. In addition, more studies should be carried out to clarify the exact molecular mechanism of IL-10 polymorphisms effects.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
WL, FK and JL designed the study, collected the materials, performed all experiments, YL drafted the manuscript. BS and HW participated in the study and performed the statistical analysis. All authors read and approved the final version manuscript.