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Department of Social and Preventive Medicine, University at Buffalo, Buffalo, NY 14214;
*
Department of Cancer Prevention, Epidemiology and Biostatistics, Roswell Park Cancer Institute, Buffalo, NY 14263;
Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, NY 10029; and
**
Division of Cancer Genetics and Epidemiology, Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC 20007
2To whom correspondence should be addressed. E-mail: mccann{at}acsu.buffalo.edu.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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(CYP17) genotype. Genetic variability in estrogen metabolism could affect lignan metabolism thereby modifying risk associations. We examined breast cancer risk, dietary lignans and CYP17 genotype among 207 women with primary, incident, histologically confirmed breast cancer and 188 controls frequency matched to cases by age and county of residence. Self-reported frequency of intake of 170 foods and beverages during the 2 y before the interview and other relevant data were collected by detailed in-person interviews. Dietary lignan intake was expressed as the sum of enterolactone and enterodiol production from foods. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by unconditional logistic regression, adjusting for age, education and other breast cancer risk factors. Women in the highest tertile of dietary lignans tended to have reduced breast cancer risk (OR 0.45, 95% CI 0.20–1.01 and OR 0.59, 95% CI 0.28–1.27, pre- and postmenopausal women, respectively). Substantially reduced risks in the highest tertile of lignans were observed for premenopausal women with at least one A2 allele (OR 0.12, 95% CI 0.03–0.50). Our results suggest that CYP17 genotype may be important in modifying the effect on breast cancer risk of exogenous estrogens, particularly for premenopausal women.
KEY WORDS: • phytoestrogens • CYP17 • breast cancer • humans
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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). They are widely distributed throughout the plant kingdom, represent the primary source of dietary phytoestrogens among non-Asian populations (2
) and may affect breast cancer etiology through several mechanisms. Lignan metabolites have been shown to affect endogenous estrogen levels through competitive inhibition of estrogen receptors as well as by increasing production of serum hormone-binding globulin (3
). Similarly, lignan supplementation (from flaxseed) has been shown to alter levels of serum 2-hydroxyestrone and 16-hydroxyestrone (4
), two estrogen metabolites that have been implicated in breast cancer etiology (5
–9
).
The epidemiologic literature concerning dietary lignans and breast cancer is sparse. Because food composition data for lignans were limited until recently, earlier studies relied on estimation of risk associated with urinary excretion of lignan metabolites. In general, these studies have shown reduced breast cancer risks associated with higher excretion of the lignan metabolites enterolactone and enterodiol (10
,11
). To our knowledge, however, the only study that has examined dietary lignan intake and breast cancer found no association of lignan intake with breast cancer (12
). The use of biomarkers in risk estimation has value; however, biomarkers tend to represent short-term exposure and may be affected by recent intake or individual variation in metabolism. Measurement of usual dietary intake of plant lignans may provide a better estimate of usual long-term exposure, which is more relevant to chronic disease etiology. Although food composition data for lignans remain somewhat limited, advances in this area have improved our ability to estimate dietary exposure of these compounds.
The cytochrome P450c17 (CYP17)3
gene encodes the cytochrome P450c17 enzyme that catalyzes ovarian and adrenal steroidogenesis (13
). CYP17 mediates the hydroxylation of pregnenolone and progesterone, which are metabolized eventually to dehydroepiandrosterone and androstenedione, a precursor of estradiol (14
). A variant, referred to as the A2 allele, involves a single base pair change in the upstream promoter region and was hypothesized to result in enhanced promoter activity (15
). This functional association with the polymorphism was not supported in an experimental study (16
). Nonetheless, two studies have noted that women with the A2 allele had higher estrogen levels. Increased levels of estrone, estradiol, testosterone, androstenedione, dehydroepiandrosterone and dehydroepiandrosterone sulfate have been reported for postmenopausal women with the A2A2 variant of CYP17 compared with women with the A1A1 genotype (17
). Similar associations have been reported for premenopausal women as well, with elevated serum estradiol and progesterone levels associated with the A2 allele (15
). It is possible that the A2 allele is in linkage disequilibrium with another functional polymorphism or that other transcription factors may interact with the polymorphism.
Genetic susceptibility to breast cancer associated with polymorphisms in CYP17 has been the focus of a few studies. In a case-control study of premenopausal breast cancer, women with at least one A2 allele had a risk of cancer twice that of women without this polymorphism (18
). Although no increase in risk of breast cancer associated with this polymorphism was observed among postmenopausal women in the Nurses’ Health Study Cohort, the authors reported that the reduction in risk associated with late age at menarche was limited to women without the A2 variant (17
). Other studies have produced less consistent findings, however, with one study reporting increased risks (19
), another increased risks in advanced breast cancer only (20
) but three others reporting no association (21
–23
).
Because of the structural similarity of enterolactone and enterodiol to estradiol, it is possible that genetic variation in CYP17 might modify the effect of phytoestrogens on endogenous estrogen levels and thus on breast cancer risk. Conversely, previous investigations have suggested that certain dietary components can act as inhibitors of gene expression (24
); it is possible that lignans may act on CYP17 in this manner. Therefore, the aim of this study was to investigate the relationship between dietary lignans and risk of breast cancer as well as modification of that risk by the CYP17 polymorphism in a case-control study of diet and breast cancer conducted in western New York between 1986 and 1991.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Data for these analyses were collected as part of a series of case-control studies of diet and cancer of the breast, endometrium, ovary and prostate in western New York. The epidemiologic methods for this study were described in detail elsewhere (25
–27
). Briefly, the breast cancer case-control study included 617 (301 cases, 316 controls; response rate 66 and 62%, respectively) premenopausal and 933 (439 cases, 494 controls; response rate 56.5 and 45.9%, respectively) postmenopausal Caucasian women from western New York. Women with primary, incident, histologically confirmed breast cancer were frequency matched by age and county of residence to controls. Controls were randomly selected from driver’s license lists for women <65 y of age and from Health Care Finance Administration lists for women 
65 y of age. The study protocol was approved by the Institutional Review Board of the University at Buffalo and all participating hospitals. Informed consent was obtained from all participants before interview.
All women were interviewed in their homes by trained nurse interviewers using a detailed interview that included questions on diet, reproductive history, family history of cancer, medical history, health habits such as cigarette smoking and physical activity, and other lifestyle and occupational factors. Diet in the year 2 y before the interview was queried using an extensive food-frequency questionnaire. Nutrient intake from foods and beverages only was calculated using food composition data from the USDA and published food composition tables (28
–30
). Lignan intake was expressed as the sum of enterolactone and enterodiol production from foods (30
). All data were self-reported. Approximately 45% of premenopausal (96 cases, 86 controls) and 63% of postmenopausal (111 cases, 102 controls) women provided blood samples.
Laboratory analysis.
DNA was obtained from frozen blood clots through purification by standard phenol/chloroform extraction followed by ethanol precipitation. Polymerase chain reaction (PCR) conditions were based on methods developed by Carey et al. (31
) in which genomic DNA (50 ng) was amplified using 50 pmol of primers (5'-CAT TCG CAC TCT GGA GTC-3' and 5'-AGG CTC TTG GGG TAC TTG-3') in GeneAmp PCR buffer (50 mmol/L KCl, 10 mmol/L Tris-HCl, pH 8.3, 0.01 g/L gelatin, 1.5 mmol/L MgCl2; Perkin Elmer, Norwalk CT), and Amplitaq DNA polymerase (2.5 U; Perkin Elmer) with 2'-deoxynucleoside-3'-triphosphates (1.87 mmol/L; Pharmacia, Piscataway, NJ) in a 50-µL reaction volume. The PCR reaction had an initial melting temperature of 94°C (5 min) followed by 30 cycles of melting (94°C; 1 min), annealing (56°C; 1 min), and extension (72°C; 1 min). An extension period of 7 min at 72°C followed the final cycle. The resulting product (459 bp) was subjected to MspA1 I digest (New England Biolabs, Beverly MA) according to manufacturer’s directions. Gel electrophoresis (2.2% agarose; Gibco BRL, Gaithersburg, MD) of the resulting fragments revealed either the A1 homozygote (459 bp), the A2 homozygote (335 and 124 bp) or the A1A2 heterozygote (459, 335 and 124 bp). Results of genotyping for the study were read from the gel by two independent investigators. At least 20% of the samples were repeated for quality control and the assay was validated by confirming polymorphic Mendelian inheritance patterns in seven human family cell lines (n = 134).
Statistical analyses.
All analyses were conducted separately for pre- and postmenopausal women using SPSS for Windows (version 10.0, Chicago, IL) and all statistical tests were two sided. To determine whether women who provided a blood sample differed in characteristics possibly important in breast cancer etiology compared with women who did not provide a blood sample, differences in mean age, education, body mass index (BMI), age at first pregnancy, age at menarche, parity, history of benign breast disease, family history of breast cancer and intakes of energy, total fat, dietary fiber, vitamin C, folate, carotenoids and lignans between these two groups were assessed with t tests. Descriptive characteristics of the study participants by CYP17 genotype were computed and differences between genotypes within cases and controls assessed with generalized linear modeling for continuous variables and 
2 for categorical variables. Major food sources of dietary lignans were identified using stepwise linear regression with dietary lignans as the dependent variable and monthly grams of each food on the food-frequency questionnaire as the independent variables.
To estimate risk associated with dietary lignans, tertiles were calculated on the basis of the distribution in the controls. Risk of breast cancer in each tertile relative to the lowest (referent) tertile of lignans was estimated by odds ratios (OR) and 95% confidence intervals (CI), calculated with unconditional logistic regression in two models. In the first model, risk was calculated adjusting for age and total energy intake. The second model was further adjusted for education, parity, BMI, history of benign breast disease, family history of breast cancer, age at menarche and age at menopause in postmenopausal women. To estimate the effect of CYP17 genotype on risk of breast cancer associated with tertile of dietary lignans, analyses were conducted as previously described, stratified by CYP17 genotype. Because of small numbers of women with the homozygous variant (A2A2) genotype, we created one category with women with the heterozygous and homozygous variant genotypes (A1A2 and A2A2).
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Comparing characteristics of breast cancer cases and controls by CYP17 genotype revealed no significant differences among either cases or controls for age, education, BMI, number of pregnancies, age at first pregnancy, age at menarche, daily lignan and energy intakes, history of benign breast disease or family history of breast cancer (Table 1
). We also computed risk of breast cancer associated with CYP17 genotype (data not shown). Compared with women with the A1A1 genotype, we observed no association of pre- or postmenopausal breast cancer risk among women with at least one A2 allele (OR 0.76, 95% CI 0.40–1.43 and OR 0.97 95% CI 0.55–1.71, pre- and postmenopausal women, respectively).
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). Three foods explained the largest amount of variability in dietary lignans: carrots (38%), broccoli (20%), and summer squash (13%). Although tomatoes and bananas are fairly poor sources of lignans, they were among the top contributors because they are consumed in relatively large quantities.
|
). Among the full study sample, significantly reduced risks of breast cancer were observed for the highest tertile of dietary lignans for both pre- and postmenopausal women (OR 0.49, 95% CI 0.32–0.75 and OR 0.72, 95% CI 0.51–1.02, pre- and postmenopausal women, respectively). Adjustment for nondietary breast cancer risk factors had little effect on the observed risk estimates. Similar findings were obtained for the subset of women who provided blood samples, although the smaller sample size resulted in a widening of the CI. Compared with women in the lowest tertile of dietary lignans, we observed a marginally significant 55% reduction in risk of premenopausal breast cancer for women in the highest tertile (OR 0.45, 95% CI 0.20–1.01). A weaker reduction in risk was observed for postmenopausal women in the highest tertile compared with the lowest, an effect that became somewhat stronger after adjustment for the nondietary risk factors (OR 0.59, 95% CI 0.28–1.27). Further adjustment for potential dietary confounders (dietary fiber, folate, carotenoids) had little effect on the observed estimates (data not shown).
|
). CYP17 genotype had little effect on risk associated with lignans among postmenopausal women, with nonsignificant OR generally ranging from 0.59 to 0.62. As in the analyses of dietary lignans with breast cancer risk, further adjustment for potential dietary confounders had little effect on the observed estimates (data not shown).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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). On the other hand, the phytoestrogen lignans are widely available in the Western diet and are present in appreciable quantities in foods commonly consumed among Western populations. In fact, in our study, the major contributors to dietary lignans were commonly consumed vegetables. Because these foods are commonly consumed, recommendations for dietary changes to reduce chronic disease risk become more accessible to the general public.
We observed important reductions in breast cancer risk associated with the highest categories of dietary lignans in these data, especially among premenopausal women. The literature examining dietary lignans and breast cancer risk is sparse. In part, this is a result of limited food composition data for these phytoestrogens. In these analyses, dietary lignans were expressed as the sum of enterolactone and enterodiol production from foods (30
). These values approximate the physiologically active lignan components that are relevant in disease etiology. Although mammalian lignan production in the gut may be susceptible to interindividual variability in metabolism, these values have been shown to correlate well with urinary lignan excretion (33
) and thus provide a reasonable estimate of the physiologically active dietary exposure to lignans.
Studies examining urinary lignan excretion and breast cancer risk have suggested that higher excretion (presumably from higher intake) may be related to reduced breast cancer risks (10
,11
). The mechanism by which lignans could affect breast cancer risk is likely through competitive inhibition of the estrogen receptor at target tissues (1
,3
), although alterations in serum hormone-binding globulins as well as serum levels of estradiol and other steroid hormones after lignan supplementation have also been reported (4
).
Our results also suggest that the effect of dietary lignans on breast cancer risk may be modified by differences in genetic susceptibility. The lignan metabolites enterolactone and enterodiol are structurally similar to estradiol. CYP17 is important in steroid metabolism; it may also be involved in phytoestrogen metabolism or may be inhibited by phytoestrogen intakes. Although the literature does not, in general, support a main effect of CYP17 genotype on breast cancer risk (17
–23
), associations with other hormone-related risk factors have been shown to differ by CYP17 genotype (17
,22
,23
,34
). In the present study, the reduction in breast cancer risk observed in the highest tertile of dietary lignans was substantially greater among women with at least one A2 allele, at least for the premenopausal women.
The mechanism for the interaction with menopausal status is unclear. The A2 allele has been associated with increased levels of serum estradiol and progesterone levels in premenopausal women (15
) and of estrone, estradiol, testosterone, androstenedione, dehydroepiandrosterone and dehydroepiandrosterone sulfate among postmenopausal women (17
). There may be a threshold effect in which lignans provide the greatest protective effect among women who have higher endogenous hormone levels, and presumably, higher breast cancer risk. Furthermore, the role of CYP17 in steroidogenesis is in the conversion of pregnenolone and progesterone to androstenedione, thus providing ample substrate for the production of estradiol (14
). Among postmenopausal women, estrogens are derived primarily from aromatization in the adipose tissue. Although some increase in androgens has been observed among postmenopausal women with the A2 allele, it may be that CYP17 plays a less important role in this mechanism among postmenopausal women.
On the other hand, the promotor activity of the A2 allele may affect serum phytoestrogen levels in a manner similar to that observed for endogenous estrogens. If serum enterolactone and enterodiol metabolite levels were higher because of a promotional effect of the A2 genotype, then a lower lignan intake could conceivably result in a larger reduction in risk.
The analyses of interaction between CYP17 and dietary lignans involved a relatively small sample size; therefore, generalizability of our results could be reduced. However, the women who provided blood samples in this study were comparable with those who did not provide blood samples in many of the characteristics found to be important in breast cancer etiology. Furthermore, risks of breast cancer estimated in the larger sample were quite similar to those in the smaller sample, suggesting that the smaller sample size was not an important source of bias.
However, we did observe somewhat higher intakes of folate, dietary fiber and lignans among women who provided blood samples than those who did not. Both folate and dietary fiber intakes have been shown to be related negatively to breast cancer in several epidemiologic studies, and both nutrients are related positively to dietary lignans. These nutrients, as well as others found in a plant-based diets, could have confounded our estimates of risks associated with dietary lignans. This did not appear to be the case in our data because further adjustment of the logistic regression models for these nutrients had little effect on our observed estimates. Although it is likely that many components of a plant-based diet contribute to lower cancer risks, our data suggest that lignans are important contributors to this effect.
Contrary to the findings of Horn-Ross (12
), we found that high dietary lignans were associated with substantial reductions in breast cancer risk, especially for premenopausal women. That study, however, included Caucasian, Latino and African-American women and did not stratify the analyses of lignan intake with breast cancer by menopausal status or race, but rather focused the stratified analyses on total phytoestrogen intake. Further investigations are necessary to clarify the relationship between dietary lignans and breast cancer.
Our study provides further evidence that genetic susceptibility is important in modifying the effect of different factors on breast cancer risk. Furthermore, our results have important implications relevant to potential mechanisms by which dietary factors with estrogenic activity may be involved in endogenous hormone metabolism and action. The literature seems to support a generally protective effect of higher lignan intake, at least the amounts that can be obtained from typical diets, and the present results imply that these effects may be greater among genetically predisposed individuals. Corroboration of these findings in other breast cancer studies, as well as in other hormone-related cancers, would add greatly to our ability to target interventions to reduce disease risk.
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FOOTNOTES |
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3 Abbreviations used: BMI, body mass index; CI, confidence interval; CYP17, cytochrome P450c17; OR, odds ratio; PCR, polymerase chain reaction.
Manuscript received 28 May 2002. Initial review completed 26 June 2002. Revision accepted 20 July 2002.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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 S. E. McCann, J. Wactawski-Wende, K. Kufel, J. Olson, B. Ovando, S. N. Kadlubar, W. Davis, L. Carter, P. Muti, P. G. Shields, et al. Changes in 2-Hydroxyestrone and 16{alpha}-Hydroxyestrone Metabolism with Flaxseed Consumption: Modification by COMT and CYP1B1 Genotype Cancer Epidemiol. Biomarkers Prev., February 1, 2007; 16(2): 256 - 262. [Abstract] [Full Text] [PDF]
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 M. T Zarrabeitia, J. L Hernandez, C. Valero, A. Zarrabeitia, J. A Amado, J. Gonzalez-Macias, and J. A Riancho Adiposity, estradiol, and genetic variants of steroid-metabolizing enzymes as determinants of bone mineral density Eur. J. Endocrinol., January 1, 2007; 156(1): 117 - 122. [Abstract] [Full Text] [PDF]
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M. S. Touillaud, A. C.M. Thiebaut, M. Niravong, M.-C. Boutron-Ruault, and F. Clavel-Chapelon No Association between Dietary Phytoestrogens and Risk of Premenopausal Breast Cancer in a French Cohort Study Cancer Epidemiol. Biomarkers Prev., December 1, 2006; 15(12): 2574 - 2576. [Full Text] [PDF]
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R. Piller, E. Verla-Tebit, S. Wang-Gohrke, J. Linseisen, and J. Chang-Claude CYP17 Genotype Modifies the Association between Lignan Supply and Premenopausal Breast Cancer Risk in Humans J. Nutr., June 1, 2006; 136(6): 1596 - 1603. [Abstract] [Full Text] [PDF]
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A. Stuedal, I. T. Gram, Y. Bremnes, H. Adlercreutz, M. B. Veierod, and G. Ursin Plasma Levels of Enterolactone and Percentage Mammographic Density among Postmenopausal Women Cancer Epidemiol. Biomarkers Prev., September 1, 2005; 14(9): 2154 - 2159. [Abstract] [Full Text] [PDF]
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I. E. J. Milder, E. J. M. Feskens, I. C. W. Arts, H. B. B. de Mesquita, P. C. H. Hollman, and D. Kromhout Intake of the Plant Lignans Secoisolariciresinol, Matairesinol, Lariciresinol, and Pinoresinol in Dutch Men and Women J. Nutr., May 1, 2005; 135(5): 1202 - 1207. [Abstract] [Full Text] [PDF]
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 I. C. Arts and P. C. Hollman Polyphenols and disease risk in epidemiologic studies Am. J. Clinical Nutrition, January 1, 2005; 81(1): 317S - 325S. [Abstract] [Full Text] [PDF]
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A. Olsen, K. E. B. Knudsen, B. L. Thomsen, S. Loft, C. Stripp, K. Overvad, S. Moller, and A. Tjonneland Plasma Enterolactone and Breast Cancer Incidence by Estrogen Receptor Status Cancer Epidemiol. Biomarkers Prev., December 1, 2004; 13(12): 2084 - 2089. [Abstract] [Full Text] [PDF]
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L. Sharp, A. H. Cardy, S. C. Cotton, and J. Little CYP17 Gene Polymorphisms: Prevalence and Associations with Hormone Levels and Related Factors. A HuGE Review Am. J. Epidemiol., October 15, 2004; 160(8): 729 - 740. [Abstract] [Full Text] [PDF]
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N. F. Johnsen, H. Hausner, A. Olsen, I. Tetens, J. Christensen, K. E. B. Knudsen, K. Overvad, and A. Tjonneland Intake of Whole Grains and Vegetables Determines the Plasma Enterolactone Concentration of Danish Women J. Nutr., October 1, 2004; 134(10): 2691 - 2697. [Abstract] [Full Text] [PDF]
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H. Hausner, N. F. Johnsen, J. Hallund, and I. Tetens A Single Measurement Is Inadequate to Estimate Enterolactone Levels in Danish Postmenopausal Women Due to Large Intraindividual Variation J. Nutr., May 1, 2004; 134(5): 1197 - 1200. [Abstract] [Full Text] [PDF]
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R. G Ziegler Phytoestrogens and breast cancer Am. J. Clinical Nutrition, February 1, 2004; 79(2): 183 - 184. [Full Text] [PDF]
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L. Keinan-Boker, Y. T van Der Schouw, D. E Grobbee, and P. H. Peeters Dietary phytoestrogens and breast cancer risk Am. J. Clinical Nutrition, February 1, 2004; 79(2): 282 - 288. [Abstract] [Full Text] [PDF]
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A. N. Begum, C. Nicolle, I. Mila, C. Lapierre, K. Nagano, K. Fukushima, S.-M. Heinonen, H. Adlercreutz, C. Remesy, and A. Scalbert Dietary Lignins Are Precursors of Mammalian Lignans in Rats J. Nutr., January 1, 2004; 134(1): 120 - 127. [Abstract] [Full Text] [PDF]
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A. Kilkkinen, L. M. Valsta, J. Virtamo, K. Stumpf, H. Adlercreutz, and P. Pietinen Intake of Lignans Is Associated with Serum Enterolactone Concentration in Finnish Men and Women J. Nutr., June 1, 2003; 133(6): 1830 - 1833. [Abstract] [Full Text] [PDF]
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S. E. McCann, J. L. Freudenheim, J. R. Marshall, and S. Graham Risk of Human Ovarian Cancer Is Related to Dietary Intake of Selected Nutrients, Phytochemicals and Food Groups J. Nutr., June 1, 2003; 133(6): 1937 - 1942. [Abstract] [Full Text] [PDF]
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