Introduction
Breast cancer is the most common malignancy affecting women worldwide and its incidence rate is increasing in both developed and developing countries in recent years [
1]. It is the second cause of cancer related mortality following lung cancer. The etiology of breast cancer has not been completely identified yet, but is thought to be multifactorial, with both environmental and genetic factors [
2].
Cyclooxygenase is also known as prostaglandin endoperoxide synthetase which plays an important role in the inflammatory process through converting arachidonic acid to prostaglandins [
3]. There are two isoforms of COX, COX-1 and COX-2. COX-1 is constitutive expressed and presents in many tissues while the inflammatory enzyme COX-2 is not detected in most normal tissues. However, COX-2 can be rapidly induced by a variety of mitogenic and inflammatory stimuli resulting in elevated levels of prostaglandins which can affect cell proliferation, apoptosis and angiogenesis, contributing to tumor occurrence and progression [
4‐
6]. In breast cancer, several studies have suggested that moderate to high COX-2 expression is related to the genesis of mammary tumors and the expression is associated with parameters of aggressive breast cancer, including large tumor size, positive axillary lymph node metastases, and HER2-positive tumor status [
7‐
10]. Targeted inhibition of COX-2 could inhibit the proliferation of breast cancer cell lines in vitro [
11].
Genetic polymorphisms in
COX-2 have been shown to alter its expression and influence the susceptibility to various carcinomas [
12‐
14], including breast cancer [
15]. The human
COX-2 gene (also known as
PTGS2) is located on chromosome 1q25.2-q25.3 and consists of 10 exons spanning 8.3 kb [
16]. More than 15 single nucleotide polymorphisms (SNPs) in
COX-2 have been identified, but the most extensively studied polymorphisms are the -765 G > C (rs20417) in the promoter and the 8473 C > T (rs5275) in the 3′UTR of
COX-2. Previous functional studies have suggested that the -765 G > C polymorphism may eliminate a Sp1-binding site but create an E2F binding site and result in altered
COX-2 expression [
12,
13]. The 8473 T > C polymorphism was shown to be associated with the alteration of mRNA level of the gene as sequences within the 3′UTR are important for message stability and translational efficiency [
17]. There are also several studies that have investigated the association between the two SNPs and breast cancer risk; however the results from these studies are inconclusive. To make a more precise estimation, Yu et al. conducted a mete-analysis on the associations between several
COX-2 polymorphisms and breast cancer risk and suggested borderline significant increased risk of breast cancer was detected for rs5277 but no significant association was observed for the -765 G > C and 8473 C > T polymorphisms [
15]. However, of the studies included in their meta-analysis, only two studies were conducted in Chinese population and none of the two studies investigated the rs5277 polymorphism since the minor allele frequency of rs5277 is very small in Chinese population [
18,
19]. Herein, in the present study, we investigated the association of the -765 G > C and 8473 C > T polymorphisms and breast cancer risk in a case-control study in a Chinese population.
Discussion
In the present study, we found a significant association between the COX-2 -765 G > C polymorphism and breast cancer risk. Compared with individuals with -765GG genotype, those with GC or GC/CC genotypes had a significantly increased breast cancer risk of 1.55 and 1.56, respectively. The risk effect was more predominant in younger individuals. Besides, we also found the COX-2 -765GC/CC genotypes were associated with lager tumor size, suggesting the variant genotypes of this polymorphism may participate in the progression of breast cancer.
Over-expression of
COX-2 is observed in a variety of human malignancies and in premalignant lesions [
21‐
23]. It is not only reported to be associated with the development of breast cancer but also plays important role in the progression of the disease. Previous functional studies suggested that the
COX-2 -765 G > C polymorphism was a functional variant and could alter
COX-2 expression, however, with inconclusive results [
12,
13]. For instance, Papafili et al. reported that -765C allele was associated with significantly reduced
COX-2 expression compared with the -765G allele and they postulated this effect to be mediated by the loss of Sp1 transcription factor binding to its cognate element [
12]. However, Szczeklik et al. further demonstrated that -765C had a functional consequence resulting in enhanced biosynthesis of prostaglandins through eliminating a Sp1-binding site but creating an E2F-binding site [
13]. Based on these findings, it would be interesting to investigate whether
the COX-2 -765 G > C polymorphism could be used as a genetic biomarker to predict cancer susceptibility and progression. In our study, we have observed that variant genotypes of the
COX-2 -765 G > C (GC/CC) were associated with increased breast cancer risk, and in patients group that were also associated larger tumor size. Our results are consistent with some studies on other malignancies. For example, Panguluri et al. reported that -765C allele was associated with an increased risk of prostate cancer in African Americans [
24], and Koh et al. demonstrated that an elevated risk of colon cancer in a Singapore Chinese population [
25]. There are also several studies on the association between the
COX-2 -765 G > C and breast cancer risk; however, the results are inconclusive. Recently, Yu et al. conducted a mete-analysis on this issue and concluded that no significant association was observed for the -765 G > C polymorphisms [
15]. However, only two studies enrolled in the mete-analysis were conducted in Chinese population [
18,
19], which seems insufficient to make a conclusive result in the population. Besides, in consideration of the role of COX-2 in breast cancer, if the polymorphism is associated with increased COX-2 activity, the observed association in our study is biologically plausible. However, there is still need to investigate the functional effect of the
COX-2 -765 G > C polymorphism in breast cancer.
In the subgroup analysis, we found the increased risk associated with the COX-2 -765 G > C polymorphism was more prominent in individuals younger than 52 years of age. As it is known, as age increases, individuals are more susceptible to many types of cancer, thus the small effect of the polymorphism may be overwhelmed. However, this observation should be interpreted with caution since we can not rule out the possibility that the number of older women in the older section have been decreased by deaths. We also observed that the COX-2 -765 GC/CC genotypes was associated with larger tumor size. As we mentioned above, over-expression of COX-2 correlated with parameters of aggressive breast cancer, including large tumor size, positive axillary lymph node metastases, and HER2-positive tumor status. A better understanding of the function of the polymorphism in breast cancer may help to reveal the mechanism underlying the associations. However, the results should be interpreted cautiously since there is the possibility that the association may due to a late stage at diagnosis. Nevertheless, if confirmed by additional studies, this polymorphism may help to accurately predict the clinical course of breast cancer.
As our study was hospital-based design, we could not rule out the possible of selection bias of subjects that may have been associated with a particular genotype. However, the genotype distributions of the
COX-2 polymorphism in our study population were similar to distributions reported in other studies [
18], and also similar to the distributions reported in the HapMap database for Han Chinese in Beijing [5.2% vs. 6.7% for -765 G > C and 20.3 vs. 19.5 for 8473 C > T]. Besides, the genotype distributions of the
COX-2 polymorphisms in our study population all conformed to HWE. Therefore, the selection bias in terms of genotype distribution would not be substantial.
In conclusion, our case-control study indicates that the COX-2 -765 G > C polymorphism has a significant influence on the occurrence and progression of breast cancer in the Chinese population. Further functional studies are still required to investigate the role of -765 G > C variation in regulating the gene expression in breast cancer. Since our sample size is moderate and the statistical power of the study is limited, therefore, large population-based prospective studies are warranted to further elucidate the impact of the COX-2 polymorphisms on breast cancer.
Competing interest
The authors declare that they have no competing interests.
Authors’ contributions
DZJ, GJ and KHF designed the research. DZJ, GJ, KHF, LD and MXB performed the experiments throughout this research. TW, ZY, ZSQ, GHT and WXJ contributed to the reagents, and participated in its design and coordination. LS and RHT analyzed the data; GJ, KHF and MXB contributed to the writing of the manuscript. Co-first authors: GJ, KHF, MXB and TW. All authors have read and approved the final manuscript.