Marine n-3 fatty acid intake, glutathione S-transferase polymorphisms and breast cancer risk in post-menopausal Chinese women in Singapore
Manuela Gago-Dominguez2,
J.Esteban Castelao,
Can-Lan Sun,
David Van Den Berg,
Woon-Puay Koh1,
Hin-Peng Lee1 and
Mimi C. Yu
USC/Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033-0800, USA and 1 Department of Community, Occupational and Family Medicine, National University of Singapore, 16 Medical Drive, Singapore 117597
2 To whom correspondence should be addressed. Tel: +1 323 865 0826; Fax: +1 323 865 0136; Email: mgago{at}usc.edu
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Abstract
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We have previously found marine n-3 fatty acids to be inversely related to post-menopausal breast cancer in Chinese women from Singapore. Post-menopausal women with high [quartiles 24 (Q2Q4)] versus low [quartile 1 (Q1)] intake exhibited a statistically significant reduction in risk of breast cancer after adjustment for potential confounders [relative risk (RR) = 0.66, 95% confidence interval (CI) = 0.50, 0.87]. Experimental studies have demonstrated a direct role for the peroxidation products of marine n-3 fatty acids in breast cancer protection. There is a suggestion that the glutathione S-transferases (GSTs) may be major catalysts in the elimination of these beneficial by-products. Therefore, we hypothesized that individuals possessing the low activity genotypes of GSTM1, GSTT1 and/or GSTP1 (i.e. the GSTM1 null, GSTT1 null and GSTP1 AB/BB genotypes, respectively) may exhibit a stronger marine n-3 fatty acidbreast cancer association than their high activity counterparts. The Singapore Chinese Health Study is a prospective investigation involving 35 298 middle-aged and older women, who were enrolled between April 1993 and December 1998. In this casecontrol analysis, nested within the Singapore Chinese Health Study, we compared 258 incident breast cancer cases with 670 cohort controls. Overall, breast cancer risk was unrelated to GSTM1 and GSTP1 genotypes. However, the GSTT1 null genotype was associated with a 30% reduced risk of breast cancer [odds ratio (OR) = 0.71, 95% CI = 0.52, 0.96]. Among women with high activity GST genotypes (i.e. GSTM1 positive, GSTT1 positive and GSTP1 AA), no marine n-3 fatty acidbreast cancer relationships were observed in either pre-menopausal or post-menopausal women at baseline. However, post-menopausal women possessing the combined GSTM1 null and GSTP1 AB/BB genotypes showed a statistically significant reduction in risk after adjustment for potential confounders (Q2Q4 versus Q1, OR = 0.36, 95% CI = 0.14, 0.94). A similar relationship was observed among women with the combined GSTT1 null and GSTP1 AB/BB genotypes (OR = 0.26, 95% CI = 0.08, 0.78).
Abbreviations: BMI, body mass index; CI, confidence interval; GST, glutathione S-transferase; OR, odds ratio; Q, quartile; RR, relative risk.
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Introduction
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We previously found marine n-3 fatty acids to be protective against breast cancer in Chinese women from Singapore (1); this association was confined to post-menopausal women. There was also a clear demonstration of a threshold effect [relative risk (RR) for quartiles 24 (Q24) versus quartile 1 (Q1) = 0.66, 95% confidence interval (CI) = 0.50, 0.87] (1). Experimental studies strongly implicate a direct role for the peroxidation products of marine n-3 fatty acids in breast cancer protection. Marine n-3 fatty acids and fish oil (which contains elevated levels of marine n-3 fatty acids) have been shown to inhibit the growth of breast cancer in vivo or in vitro and this inhibition is correlated with the extent of lipid peroxidation generated in tumor tissues or cells (25). Furthermore, this suppression of cancer growth is eliminated by antioxidants and this elimination is proportional to the inhibition of lipid peroxidation products by antioxidants (25). It is likely, therefore, that differences in the ability to protect cells from cytotoxic lipid peroxidation products will determine, to some degree, the protective effect of marine n-3 fatty acids on breast cancer. Because the glutathione S-transferases (GSTs) are potential major catalysts in the elimination of these beneficial by-products, we hypothesized that women possessing low activity GST genotypes (GSTM1 null, GSTT1 null and GSTP1 AB/BB) might exhibit a stronger marine n-3 fatty acidbreast cancer inverse association than those possessing the high activity genotypes. In this report we use data from the Singapore Chinese Health Study to examine the association between marine n-3 fatty acid intake and its interaction with GSTM1, GSTT1 and GSTP1 genotypes and breast cancer risk in post-menopausal Chinese women.
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Materials and methods
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Study population
The subjects were participants in the Singapore Chinese Health Study, a population-based, prospective investigation of diet and cancer risk. From April 1993 to December 1998 a total of 63 257 Chinese women and men aged 4574 years were enrolled in the study (only women are included in this report) (6). We restricted study subjects to the two major dialect groups of Chinese in Singapore, Hokkien and Cantonese. The subjects were residents of government housing estates; 86% of the Singapore population resided in these facilities during the enrollment period. At recruitment, a face-to-face interview was conducted in the subject's home by a trained interviewer, using a structured questionnaire which requested information on demographics, lifetime use of tobacco, usual physical activity, menstrual and reproductive history (women only), medical history and family history of cancer. The questionnaire also included a dietary component assessing current intake patterns, which were subsequently validated against a series of 24 h diet recalls (6).
Between April 1994 and July 1999 we attempted to collect blood (or buccal cells) and single void urine specimens from a random 3% sample of study enrollees. A 20 ml blood sample was obtained from each consenting subject. Immediately after blood collection the tubes were put on ice during transport from the subjects' homes to the laboratory. All specimens were then separated into their various components (plasma, serum, red blood cells and buffy coat). All specimens were subsequently stored in a liquid nitrogen tank at 180°C until August 2001, when they were moved to a 80°C freezer for long-term storage. If the subject refused to donate blood, he/she was asked to donate buccal cells, which were collected through the use of a modified mouthwash protocol based on published methods (7,8). Briefly, the subject was provided with a new toothbrush and asked to clean her teeth thoroughly. After an interval of 20 min, during which no food or drink was consumed, she was given 10 ml of commercially purchased Listerine mouthwash and asked to swish the liquid vigorously in her mouth for 60 s. The mouthwash was then collected in a sterile 50 ml polypropylene tube, put on ice and brought back to the laboratory within 5 h, where it was stored at 30°C. Out of 1059 female cohort participants contacted for biospecimen donation, blood (n = 514) or buccal cells (n = 164) were collected from 678 subjects, representing a participation rate of 64%. The control group for the present study consisted of the 670 women who remained free of breast cancer as of 30 April 2002. At baseline, 204 women were pre-menopausal and 466 were post-menopausal.
We identified incident breast cancer cases through the population-based cancer registry in Singapore (9). As of 30 April 2002, 399 cases of incident breast cancer had developed among female cohort subjects. Histological and staging information of all breast cancer diagnoses were confirmed by manual review of the pathology reports and clinical charts. Blood (n = 198) or buccal (n = 60) specimens were available on 258 (65%) breast cancer cases. Of these 258 cases of breast cancer, 33 cases had in situ cancers, 68 had stage I, 110 had stage II, 23 had stage III and 18 had stage IV tumors, while staging information was unavailable on 6 cases. The 151 cases who had stage II or higher tumors (regional and metastastic disease) were classified hereafter as advanced disease. Breast cancer cases who did not give a blood or buccal cell sample were less educated than those who provided such a sample (44 versus 30% had no formal education). More Cantonese donated specimens (69%) compared with Hokkien (60%). The two groups were otherwise similar with respect to age at cancer diagnosis (mean 61 versus 59 years). Seventy-eight patients were pre-menopausal at baseline; the remaining 180 were post-menopausal at baseline.
Informed consent forms were completed by all participants at baseline interview and at time of collection of blood (or buccal cells) and urine specimens. The Institutional Review Boards at the University of Southern California and the National University of Singapore had approved this study.
Baseline diet
The development and validation of the Singapore Chinese Health Study food frequency questionnaire have been described (6). At recruitment, information on usual diet over the last year was obtained via this semi-quantitative food frequency questionnaire, which was administered in person at the subject's home. The questionnaire listed 165 food and beverage items and the respondent was asked to select from eight food frequency categories (ranging from never or hardly ever to two or more times a day) and three portion sizes with accompanying photographs. The food frequency questionnaire listed 14 seafood items commonly consumed by Chinese in Singapore, including fresh fish (fish ball or cake, deep fried fish, pan or stir fried fish, boiled or steamed fish), fresh shellfish (shrimp or prawn, squid or cuttlefish), dried/salted fish (salted fish, ikan bilis, dried fish, other dried seafoods such as dried shrimp, dried oyster, dried cuttlefish) and canned fish (canned tuna, canned sardine). Average daily intake of roughly 100 nutritive and non-nutritive compounds, including marine n-3 fatty acids, was computed for each study subject via linkage to the Singapore Food Composition Database. In data analysis all foods and nutrients were expressed as weight per 1000 kcal or % kcal to adjust for total energy intake.
GSTM1, GSTT1 and GSTP1 genotype determination
Genomic DNA was isolated using a PureGene Blood Kit (Gentra Systems, Minneapolis, MN) or a QIAamp 96 DNA Blood Kit (Qiagen, Valencia, CA). Genotyping for GSTM1, GSTT1 and GSTP1 was performed using the fluorogenic 5'-nuclease assay (TaqMan Assay) (10).
The TaqMan assays were performed using a TaqMan PCR Core Reagent kit (Applied Biosystems, Foster City, CA) according to the manufacturer's instructions. The oligonucleotide primers for amplification of the polymorphic region of GSTP1 were GC070for (5'-CCTGGTGGACATGGTGAATG-3') and GC070rev (5'-TGCTCACACCATAGTTGGTGTAGATGA-3'). In addition, the fluorogenic MGB oligonucleotide probes used to detect each of the alleles were GC070F (5'-TGCAAATACGTCTCCCT-3') labeled with 6-FAM and GC070V (5'-TGCAAATACATCTCCCT-3') labeled with VIC (Applied Biosystems). PCR amplification using
10 ng genomic DNA was performed in a thermal cycler (MWG Biotech, High Point, NC) with an initial step of 95°C for 10 min followed by 50 cycles of 95°C for 25 s and 60°C for 1 min. The fluorescence profile of each well was measured in an ABI 7900HT Sequence Detection System (Applied Biosystems) and the results analyzed with Sequence Detection Software (Applied Biosystems). Experimental samples were compared with 12 controls to identify the three genotypes at each locus. Any samples that were outside the parameters defined by the controls were identified as non-informative and were retested.
Genotyping of the GSTT1 and GSTM1 loci using the TaqMan assay consisted of separate assays for GSTT1, GSTM1 and the albumin control gene. The oligonucleotide primers for amplification of the GSTT1, GSTM1 and albumin genes were GC003for (5'-GTGCAAACACCTCCTGGAGAT-3') and GC003rev (5'-AGTCCTTGGCCTTCAGAATGA-3'), GC004for (5'-CTTGGAGGAACTCCCTGAAAAG-3') and GC004rev (5'-TGGAACC TCCATAACACGTGA-3') and GC005for (5'-CGATTTTCTTTTTAGGGCAGTAGC-3') and GC005rev (5'-TGGAAACTTCTGCAAACTCAGC-3'), respectively. Fluorescent oligonucleotide probes, for detection of PCR reaction products, were synthesized to contain the dye 6-FAM (BioSearch Technologies, Novato, CA). The probes for the GSTT1, GSTM1 and albumin genes were GC003FAM (5'-ATGCTGCCCATCCCTGCCC-3'), GC004FAM (5'-AAGCGGCCATGGTTTGCAGG-3') and GC005FAM (5'-CGCCTGAGCCAGAGATTTCCCA-3'), respectively. PCR amplification using
10 ng genomic DNA was performed in an ABI 7900HT Sequence Detection System (Applied Biosystems) with an initial step of 95°C for 10 min followed by 50 cycles of 95°C for 25 s and 60°C for 1 min. The fluorescence profile of each well was measured in real time during PCR amplification and the results analyzed with Sequence Detection Software (Applied Biosystems). Any sample with a fluorescence signal that crossed a threshold of 0.2
Rn before cycle 40 was considered positive for the loci analyzed. Samples negative for both GSTT1 and GSTM1 must be positive for albumin to be called, otherwise the sample was designated non-informative and re-tested. All analyses were carried out blind to case or control status.
Statistical analysis
Unconditional logistic regression analysis (11) was used to obtain odds ratios (ORs) and their 95% CI for associations between marine n-3 fatty acid intake, GST genotype and breast cancer, separately for pre- and post-menopausal women at baseline. For marine n-3 fatty acid intake, subjects were categorized based on quartile distribution values among all female cohort members. For analysis of genotype, we compared null versus non-null genotypes of GSTM1 and GSTT1 and the GSTP1 AB and BB genotypes against the putative high activity (AA) genotype. In all regression models the following variables were included as co-variates: age at recruitment, year of recruitment, dialect group (Cantonese, Hokkien), level of education (no formal education, primary school only, secondary school or higher), number of live births (0, 12, 34, 5+) and age when periods became regular (
12, 1314, 1516, 17+ years or irregular). Inclusion of body mass index (BMI) (<20, 20<24, 24<28 or
28 kg/m2) in multivariate models did not appreciably alter the marine n-3 fatty acidbreast cancer association. Therefore, all ORs in this report were unadjusted for BMI.
Statistical analysis was carried out using SAS software version 8.2 (SAS Institute, Cary NC). All P values reported are two-sided and P values <0.05 were considered statistically significant. In all analyses subjects with non-informative genotypes were excluded.
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Results
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Among women in the Singapore Chinese Health Study, factors positively associated with risk were level of education, BMI (in post-menopausal women), age at first giving birth and family history of breast cancer. Factors inversely associated with risk were age when periods became regular and number of live births (12). Smoking was a relatively uncommon event among our study subjects; only 58 (6%) women reported to be smokers in our population (15 cases, 43 controls). No association was found between breast cancer risk and smoking status, number of cigarettes per day or number of years of smoking.
The prevalences of the GSTM1 null and GSTT1 null genotypes among controls were 45 and 42%, respectively, and those of the GSTP1 AB and BB genotypes were 30 and 4%, respectively. Overall, there were no associations between GSTM1 and GSTP1 genotype and breast cancer risk. The OR for the GSTM1 null versus non-null genotype was 1.05 (95% CI = 0.78, 1.41) and those for the GSTP1 AB/BB genotypes relative to the putative high activity AA genotype were 1.19 (95% CI = 0.87, 1.64) and 0.97 (95% CI = 0.44, 2.13), respectively. However, the GSTT1 null genotype was associated with a 30% reduced risk of breast cancer (OR = 0.71, 95% CI = 0.52, 0.96).
We examined the marine n-3 fatty acidbreast cancer association stratified by GSTM1, GSTT1 and GSTP1 genotypes individually among post-menopausal women at baseline (Table I). A stronger protection was consistently found in the low than high activity genotype subgroups. While none of the associations in the high activity genotype subgroups was statistically significant, risk of breast cancer in high (Q2Q4) versus low (Q1) consumers of marine n-3 fatty acids was halved among women possessing either the GSTT1 null genotype (borderline statistically significant) or the GSTP1 AB/BB genotype (statistically significant) (Table I).
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Table I. Dietary intake levels of marine n-3 fatty acid in relation to risk of post-menopausal breast cancer by GSTM1, GSTT1 and GSTP1 genotypes individually (The Singapore Chinese Health Study)
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Table II shows the marine n-3 fatty acidbreast cancer association stratified by GSTM1, GSTT1 and GSTP1 genotypes in pairwise combination among post-menopausal women at baseline. Again, individuals belonging to the lower versus higher activity genotype subgroups consistently exhibited a stronger fatty acidbreast cancer inverse association. While there were no statistically significant associations in the high activity genotype subgroups, among women possessing the GSTM1 null and GSTP1 AB/BB genotypes, high (Q2Q4) consumers of marine n-3 fatty acids showed a statistically significant 64% reduction in RR with respect to low (Q1) consumers. The corresponding risk was even lower (OR = 0.26, 95% CI = 0.08, 0.78) among women with the GSTT1 null and GSTP1 AB/BB genotypes (Table II).
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Table II. Dietary intake levels of marine n-3 fatty acid in relation to risk of post-menopausal breast cancer by GSTM1, GSTT1 and GSTP1 genotypes in pairwise combination (The Singapore Chinese Health Study)
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We repeated the above-described analysis for pre-menopausal women at baseline; no evidence of risk modification was found. We also found no evidence that this genediet interaction effect was modified by stage of disease (localized versus advanced breast cancer).
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Discussion
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In the present study we found that women with genetic polymorphisms encoding lower or no enzymatic activity of GSTM1, GSTT1 and/or GSTP1 experienced more breast cancer protection from marine n-3 fatty acids than those with high activity genotypes, consistent with the hypothesis that the peroxidation products of n-3 fatty acids are directly involved in breast anticarcinogenesis and that they are substrates for the GSTs. The problem of multiple testings is an inherent limitation of all epidemiological studies, which can lead to false positive results. However, internal consistency within the study dataset and the biological plausibility of the study results are powerful arguments in favor of a causal interpretation. In the present study we have internally consistent observations; all three GST low activity genotypes were associated with a lower risk. Furthermore, there is strong laboratory evidence in support of the peroxidation products of n-3 fatty acids being the proximal anticarcinogens in breast cancer protection (see below).
The following lines of evidence support the notion that cytotoxic lipid peroxidation products are the proximal anticarcinogens responsible for the decreased breast cancer risk associated with marine n-3 fatty acids. (i) In experimental studies, marine n-3 fatty acids and fish oil have been shown to inhibit the growth of breast cancer in vivo or in vitro, and this inhibition is a function of increased lipid peroxidation (25). (ii) This suppression of cancer growth is enhanced by drugs that increase lipid peroxidation (2,13). (iii) This suppression of cancer growth is eliminated by antioxidants, and this elimination is proportional to the extent of inhibition of lipid peroxidation by antioxidants (25). (iv) In humans a number of clinical studies have shown that patients treated with marine n-3 fatty acids have marked increases in lipid peroxidation products (1416).
Glutathione-associated metabolism is a major mechanism for cellular protection against agents that generate oxidative stress, by eliminating cytotoxic products of lipid peroxidation (17). GSTs are induced under conditions of oxidative stress (17,18) and they are active in the detoxification of organic epoxides, hydroperoxides and unsaturated aldehydes, including reactive purine and pyrimidine bases and lipid peroxides produced by reactive oxidant damage to DNA and lipids, respectively (17,19). Therefore, women possessing the low activity GST genotypes may have a reduced capacity to remove the oxidative products of marine n-3 fatty acids and, thus, may experience a higher level of breast cancer protection, as supported by results from the present study.
Overall, GSTM1 and GSTP1 genotypes were unrelated to breast cancer risk in the present study. However, the GSTT1 null genotype was associated with a 30% reduced risk of breast cancer. This finding is consistent with that of Garcia-Closas et al. (20), who reported a decreased breast cancer risk for pre-menopausal women lacking the GSTT1 gene. For the most part, studies have found no increased risk for breast cancer with null genotypes for GSTM1 and/or GSTT1 (reviewed in 21), although there have been some positive findings (2226). The overall null effects of GSTM1 and GSTP1 found in the present study may reflect their actions on carcinogens for breast cancer.
The current study has several strengths. Singapore is a small city-state where there is good access to specialized medical care. The nationwide cancer registry has been in place since 1968 and has been shown to be comprehensive in its recording of cancer cases (27). Thus, breast cancer case ascertainment can be assumed to be complete. Our study subjects originated from two contiguous regions in South China, leading to a high degree of genetic homogeneity. The study allows for the adjustment of known environmental risk factors for breast cancer, all of which were assessed prior to cancer diagnosis and thus can be presumed to be free of recall bias.
Limitations of the present study include the relatively short duration of follow-up of the Singapore Chinese Health Study cohort and the resultant relatively small number of breast cancer cases. However, more cases will accrue over time within the cohort to definitively address this novel geneenvironment interaction.
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Acknowledgments
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We thank Ms Siew-Hong Low of the National University of Singapore for supervising the fieldwork of the Singapore Chinese Health Study and Ms Kazuko Arakawa of the University of Southern California for the development and management of the cohort study database. The Singapore Chinese Health Study has been supported by grants R01 CA55069, R35 CA53890 and R01 CA80205 from the National Cancer Institute, Bethesda, MD.
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Received February 18, 2004;
revised May 18, 2004;
accepted July 6, 2004.