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Human Cancer Biology

Interleukin-1 and -6 Polymorphisms and the Risk of in Caucasian Women Lukas A. Hefler,1, 3 Christoph Grimm,1Tilmann Lantzsch,4 Dieter Lampe,4 Sepp Leodolter,1, 3 Heinz Koelbl,5 Georg Heinze,2 Alexander Reinthaller,1Dan Tong-Cacsire,1Clemens Tempfer,1, 3 and Robert Zeillinger1, 3

Abstract Purpose: Genetic polymorphisms of -encoding are known to predispose to malignant disease. Interleukin (IL)-1and IL-6 are crucially involved in breast carcinogenesis. Whether polymorphisms of the genes encoding IL-1 (IL1)andIL-6(IL6) also influence breast cancer risk is unknown. Experimental Design: In the present case-control study, we ascertained three polymorphisms of the IL1 gene cluster [889 C/T polymorphism of the IL1agene (IL1A), 511C/T polymorphism of the IL1b promoter (IL1B promoter), a polymorphism of IL1b exon 5 (IL1B exon 5 )], an 86-bp repeat in intron 2 of the IL1 receptor antagonist gene (IL1RN), and the 174 G/C polymorphism of the IL6 gene (IL6 ) in 269 patients with breast cancer and 227 healthy controls using PCR and pyrosequencing. Results: Polymorphisms within the IL1 gene cluster and the respective haplotypes were not associated with the presence and the phenotype of breast cancer. The IL6 polymorphism was significantly associated with breast cancer. Odds ratios for women with one or two high-risk alleles versus women homozygous for the low-risk allele were 1.5 (95% confidence interval, 1.04-2.3; P = 0.04) and 2.0 (95% confidence interval, 1.1-3.6; P = 0.02), respectively. No associ- ation was ascertained between presence of the IL6 polymorphism and various clinicopathologic variables. Conclusions: Although polymorphisms within the IL1 gene cluster do not seem to influence breast cancer risk or phenotype, presence of the 174 C IL6 allele increases the risk of breast cancer in Caucasian women in a dose-dependent fashion.

The interleukin-1 (IL-1) family consists of the two proin- With respect to breast cancer, in vitro studies showed that IL-1 flammatory IL-1a and IL-1h (1, 2). IL-1a and IL-1h inhibits malignant cell growth by reducing the ability of are produced by , , and epithelial cells -like I mediated DNA-synthesis (3). and exhibit similar biological characteristics including host Interestingly, other in vitro studies showed that IL-1 is an response to microbial invasion, , and tissue injury autocrine and paracrine inducer of prometastatic genes (4). In (1). The activity of IL-1a and IL-1h is modulated by an human breast cancer, an important role of IL-1 and IL-1RA endogenous IL-1 inhibitor, i.e., IL-1 receptor antagonist expression was noted in various studies (5–7). These studies (IL-1RA), by binding to the IL-1 receptor without exerting an suggest that the IL-1 system is vital in the local control of tumor effector function (2). growth (6), important in regulating ‘‘protumorigenic’’ activities within the (7), and contributes to angiogenesis, tumor proliferation, and tumor invasion (5). IL-6, a phosphorylated glycoprotein containing 185 amino Authors’ Affiliations: 1Department of Obstetrics and Gynecology, 2Core Unit for acids, is a pleiotropic cytokine involved in different physiologic Medical Statistics and Informatics, Medical University of Vienna, and 3Ludwig and pathophysiologic processes such as inflammation, Boltzmann Institute for Gynecology and Gynecologic Oncology,Vienna, Austria; metabolism, synthesis of C-reactive protein, and carcinogenesis 4Departments of Obstetrics and Gynecology, Martin-Luther-University Medical School Halle-Wittenberg, Halle; and 5Johannes Gutenberg-University Mainz, (8, 9). IL-6 has also been shown to inhibit the growth of Mainz, Germany various breast cancer cell lines (10), shows antiadhesive effects Received 1/1/05; revised 5/7/05; accepted 5/26/05. (11), and modulates the estrogen receptor and progesterone Grant support: Ludwig Boltzmann Institute of Gynecology and Gynecologic receptor content of these cells (12). IL-6 is thought to increase Oncology,Vienna, Austria. the activity of the 17-h-hydroxysteroid dehydrogenase, which The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance converts estrone to estradiol, a process that may contribute to with 18 U.S.C. Section 1734 solely to indicate this fact. the increased concentration of estrogen around breast tumors Requests for reprints: Lukas A. Hefler, Department of Obstetrics and (13). Furthermore, IL-6 has been shown to be involved in Gynecology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 intercellular signaling between mesenchyme and breast cancer Vienna, Austria. Phone: 43-1-40400-2962; Fax: 43-1-40400-2911; E-mail: [email protected]. . These findings from in vitro studies extend to F 2005 American Association for Cancer Research. human breast cancer as elevated serum IL-6 levels were found doi:10.1158/1078-0432.CCR-05-0001 to be independent prognosticators (14, 15). Of note, both ILs,

Clin Cancer Res 2005;11(16) August 15, 2005 5718 www.aacrjournals.org Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2005 American Association for Cancer Research. IL-1andIL-6GenePolymorphismsandBreastCancer i.e., IL-1 and IL-6, have been shown to strongly interact (16) IL1 gene locus, we did haplotype analysis and repeated the associ- and to act additively in breast carcinogenesis, subsequently ation analysis on the haplotype level using permutation analysis. inhibiting tumor growth (12, 13). P values <0.05 were considered statistically significant. For statistical The human genes encoding IL-1a (IL1A), IL-1h (IL1B), and analysis, we used the SPSS statistical software system (SPSS 11.0, IL-1RA (IL1RN) are located within a 430 kb region on SPSS Inc., Chicago, IL) and SAS/Genetics V9.1 (2003 SAS Institute Inc., Cary, NC). 2q14.2 (17). Polymorphisms of IL1A, IL1B, and IL1RN correspond with altered IL-1a, IL-1h,andIL-1RA protein expression in vitro and in vivo, respectively (18–22). Results The human IL-6 gene (IL6) is mapped to chromosome 7p21-24 pT1, pT2, pT3, and pT4 tumors were found in 140, 99, 12, with an upstream promoter containing 303 bp (23). The 18, respectively. G1, G2, and G3 tumors were found in 20, 150, common 174 G/C IL6 polymorphism has also been shown to and 99 cases, respectively. Histologically, 185 tumors were influence in vivo protein expression by reducing transcription graded as ductal, 33 as lobular, 5 as tubular, 4 as cribriforme, 9 rates (24, 25). These IL1 and IL6 polymorphisms have been as medullary, 5 as mucinous carcinoma, 6 as undifferentiated, 3 linked to various malignancies such as gastric (26), hepato- as scirrhous, 5 as papillotubular, and 14 other histologic types cellular (27), lung (28), colorectal (29), vulvar (30), and of breast cancer. One hundred and forty-six patients were ovarian cancer (31). –negative whereas 110 patients were lymph node– Although few studies have been published to date with positive; lymph node status was unknown in 13 patients. respect to polymorphisms within the IL1 gene cluster and Estrogen and progesterone receptor positivity was noted in 196 breast cancer (32), the data on the 174 G/C IL6 polymor- and 173 tumors, respectively. phism in breast cancer are controversial. DeMichele et al. Hardy-Weinberg equilibrium was tested for the 889 C/T reported that the presence of the IL6 polymorphism was IL1A (P = 0.2, P = 0.01), the 511 C/T IL1B promoter (P = 0.5, associated with an improved outcome in high-risk breast P = 0.5), the IL1B exon 5 (P = 0.7, P = 0.04), the IL1RN (P = cancer (33), whereas Iacopetta et al. showed that the IL6 0.05, P = 0.2), and the 174 G/C IL6 (P = 0.5, P = 0.9) polymorphism was predictive of an aggressive breast cancer genotypes in patients with breast cancer and controls. phenotype (34). Unadjusted odds ratios (95% CI) and the respective P values Based on the important role of IL-1 and IL-6 and their crucial are shown in Table 1. No significant associations were interaction in breast carcinogenesis, the previously published ascertained between 889 C/T IL1A, 511 C/T IL1B promoter, associations of IL1 and IL6 polymorphisms with various malignant diseases, and data on 174 G/C IL6 polymorphism in breast cancer, we hypothesized that IL1 and IL6 poly- morphisms influence breast cancer risk in Caucasian women. Table 1. Genotype frequencies of the IL1A, IL1B promoter,IL1Bexon5,IL1RN,andIL6 polymorphisms Materials and Methods Breast Controls P Odds ratio Approval for this study was obtained by the Institutional Review cancer (95% CI) Boards at the Martin-Luther-University Medical School, Halle- Wittenberg, Germany and the Medical University of Vienna, Vienna, IL1A Austria. Two hundred and sixty-nine consecutive patients with breast 889 C/C 123 102 1.0 cancer treated between 1999 and 2001 at the Departments of Obstetrics 889 C/T 124 112 0.7* 0.9 (0.6-1.3)* c c and Gynecology, Martin-Luther-University Medical School, Halle- 889 T/T 22 13 0.5 1.4 (0.7-2.9) Wittenberg, Germany and at the Medical University of Vienna, Vienna, IL1B promoter Austria, were included in our study. Enrollment of cases and controls 511C/C 124 88 1.0 was started in November 1999 and ended in January 2003. Rejection 511C/T 114 111 0.1* 0.7 (0.5-1.1)* rates of cases and controls were 1.3% and 4.2%, respectively, mostly 511T/T 31 28 0.5c 0.8 (0.4-1.4)c due to language difficulties. All patients were of Caucasian origin and consented to participating in our study. Histologic staging of breast IL1B exon 5 cancer was done according to the current classification of the E1/E1 159 119 1.0 International Union Against Cancer. Healthy Caucasian women from E1/E 2 97 9 9 0.1 * 0.7 (0. 5 -1.1) * the same geographic area without breast cancer in their personal E2/E2 13 9 1.0c 1.1 (0.5-2.6)c histories (n = 228) were used as controls. These women were visiting IL1RN outpatient departments, mostly seeking counseling for various reasons, I/I 145 111 1.0 mainly for postmenopausal disorders or risk assessment for malignan- I/II 96 89 0.3* 0.8 (0.6-1.2)* cies. No difference in age was ascertained between patients with breast II/II 18 15 0.9c 0.9 (0.4-1.9)c cancer and controls [54.9 (12.5) versus 53.3 (10.2) years, respectively, b b Others 10 12 0.2 0.5 (0.2-1.3) P = 0.1]. Signed written consent was obtained from all participating IL6 women. To avoid confounding by ethnicity, only women of Austrian and German ethnic background were included. 174 G/G 78 91 1.0 DNA was extracted from patients’ blood. Pyrosequencing and PCR 174 G/C 139 105 0.04* 1.5(1.04-2.3)* c c were done according to established protocols as described previously 174 C/C 52 31 0.02 2.0 (1.1-3.6) (35, 36). m2 Where appropriate, analysis was done. Odds ratios and 95% *m2 test, a heterozygous versus wild-type calculation was done. confidence intervals (CI) are given accordingly. For statistical analyses cm2 test, a homozygous versus wild-type calculation was done. with respect to the IL6 polymorphism, we used a genotype model bm2 test, other genotypes versus wild-type calculations was done. (IL6 174 G/G versus IL6 174 G/C versus IL6 174C/C). Within the

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IL1B exon 5, and IL1RN, and the presence of breast cancer. A related to tumor stage and lymph node involvement. With re- test for marker-trait association showed no significant associ- spect to genotype frequencies of the controls, our results com- ation between the 16 haplotypes within the IL1 gene family pare favorably with those previously published for Caucasians and the presence of breast cancer (P = 0.7). The 174 G/C (42–44). Of note, the investigated polymorphisms were not all polymorphism was associated with the presence of breast in Hardy-Weinberg equilibrium. This finding is surprising. Of cancer in a dose-dependent fashion. Odds ratios for women note, the genotyping procedures used in the present study have with one and two polymorphic alleles versus women with a been rigorously validated and were previously used in various wild-type genotype were 1.5 (95% CI 1.04-2.3, P = 0.04) and studies. Furthermore, we selected women as controls, only if 2.0 (95% CI 1.1-3.6, P = 0.02), respectively. they were healthy Caucasian women from the same geographic No associations between the investigated polymorphisms area without breast cancer in their personal histories after 889 C/T IL1A (P = 0.3, P = 0.6, P = 0.9, P = 0.9, P = 0.5), 511 assessing a detailed medical history. Therefore, we can exclude C/T IL1B promoter (P = 0.06, P = 0.06, P = 0.6, P = 0.4, any bias with respect to selection of controls and the P = 0.2), IL1B exon 5 (P = 0.3, P = 0.07, P = 0.2, P = 0.9, P = 0.2), genotyping procedure. the IL1RN (P = 0.5, P = 0.6, P = 0.8, P = 0.2, P = 0.3), and 174 Our data seem promising with respect to the 174 G/C IL6 G/C IL6 (P = 0.7, P = 0.9, P = 0.3, P = 0.3, P = 0.3) and the polymorphism. As previously published for other malignancies clinicopathologic variables, tumor stage, lymph node involve- (29), the 174 G/C IL6 polymorphism likely is important ment, tumor grade, presence of estrogen, and progesterone for carcinogenesis. Previously published data are conflicting receptor were noted in our series. (34, 35). We cannot confirm data on the association between the IL6 polymorphism and clinicopathologic variables. Fur- Discussion thermore, our study cannot comment on the prognostic impact of the IL6 polymorphism, as patient follow-up is incomplete. As prophylactic interventions in order to reduce breast cancer Of note, this was not the aim of the present study. risk have gained rising popularity, the clinical importance of We provide new data with respect to a significant association breast cancer risk assessment has increased dramatically in between the IL6 polymorphism and breast cancer. To imply recent years (37, 38). Testing of mutations and polymorphisms causality, findings from association studies should be discussed in candidate genes of breast cancer has been proposed as a along the Bradford Hill criteria (45): (a) temporality, (b) powerful tool in assessing an unaffected woman’s personal risk strength, (c) consistency, (d) biological gradient, (e) specificity, for disease (39–41). (f) biological plausibility, and (g) analogy. Our results are in Although numerous genetic association studies dealing with accordance with most of these criteria. The IL6 polymorphisms breast cancer have been published, few candidate genes for this are inherited (a), therefore present before eventual breast disease have been established. Cytokines in general are thought cancer occurs; a doubling of risk was ascertained with two to be involved in numerous physiologic and pathologic mutant alleles present (b); the results are in accordance with conditions. Among cytokines, IL-1 and IL-6 probably seem to previously published studies in other malignancies (c and g; play the most important role in breast carcinogenesis (12, 13). ref. 29); a dose-dependent effect was noted (d). Our results are IL-1 and IL-6 strongly interact with each other and act also biologically plausible (f). The 174 G/C IL6 polymor- synergistically, subsequently increasing their effect. A number phism is known to reduce gene transcription rate subsequently of well-defined gene polymorphisms within the IL1 gene cluster reducing protein levels. IL-6 is known to inhibit tumor cell and the IL6 gene have already been linked to various malignant growth. Therefore, it is not surprising that women with diseases (26–31). Although data with respect to the 174 G/C decreased protein expression are at an increased risk for IL6 polymorphism in breast cancer have been published, no developing breast cancer. It is not surprising that a gene data are available whether IL1 and IL6 gene polymorphisms can polymorphism cannot meet the ‘‘specificity’’ criterion, as the serve as ‘‘candidate genes’’ for breast cancer. IL6 gene and the encoded protein IL-6 are involved in a wide Our relatively large case-control trial in Caucasian women variety of conditions and diseases. falls short of showing any significant effect of IL1 gene poly- We present data on a novel, biologically plausible ‘‘candidate morphisms on breast cancer risk. Only a statistical trend was gene’’ for breast cancer. The presence of the 174 G/C IL6 ascertained when the 511 C/T IL1B promoter was associated polymorphism increases the risk of breast cancer in a dose- with the phenotype of breast cancer, as this polymorphism was dependent fashion.

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Lukas A. Hefler, Christoph Grimm, Tilmann Lantzsch, et al.

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