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Division of Cancer Prevention and Population Science, Roswell Park Cancer Institute, Buffalo, NY;
* Department of Social and Preventive Medicine, University at Buffalo, Buffalo, NY; and
Division of Cancer Genetics and Epidemiology, Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC
1To whom correspondence should be addressed. E-mail: christine.ambrosone{at}roswellpark.org.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • breast cancer • cruciferous vegetables • isothiocyanates • glutathione S-transferases • women
Data from epidemiologic studies indicate that diets high in vegetables reduce the risk of aerodigestive cancers (1), and may be associated with decreased risk of other cancers, including breast cancer (2). A recent meta-analysis (2) of 14 case-control studies and 3 cohort studies found that high vs. low vegetable consumption was associated with a 25% reduction in risk, but these findings were not corroborated in a pooled analysis of 8 cohort studies (Pooling Project) by Smith-Warner et al. (3).
Vegetable consumption could reduce breast cancer risk by numerous mechanisms, specific to particular vegetable families, including sources of carotenoids, vitamins A, E, and C, minerals such as selenium, and such compounds as isoflavones and lignans. Glucosinolates, found in cruciferous vegetables, may be important anticarcinogens. Interestingly, although the Pooling Project found no overall effects of total vegetable consumption on breast cancer risk, there were inverse, although nonsignificant, associations between risk and high consumption of the cruciferous vegetables, broccoli and brussels sprouts. Similarly, although total vegetable consumption did not decrease breast cancer risk in a large case-control study in Sweden (4), inverse associations were noted between risk and intake of cruciferous vegetables.
The anticarcinogenic effects of cruciferous vegetables may derive from the glucosinolates they contain; these are degraded into indoles and isothiocyanates. Indoles were studied in relation to breast cancer partly because of their effects on estrogen metabolism (5), and isothiocyanates (ITCs)2 are chemopreventive agents in animal models, perhaps due in part to their potent effects on inhibition of phase I and induction of phase II enzymes (6).
Because ITCs, particularly sulforaphane, affect phase II enzyme activity and are also substrates for glutathione S-transferases (GSTs), the role of GSTM1 and GSTT1 polymorphisms was examined in relation to ITCs and the risk of adenomas and cancers of the colon and lung. In the majority of these studies, GST genotypes modified relations between ITCs and risk (7–10), with stronger inverse associations noted for those with high consumption and null genotypes, although 1 study found no association between colon cancer and GSTM1 genotype (11).
In this study, specifically designed to evaluate associations between diet and risk of breast cancer, we investigated the effects of consumption of cruciferous vegetables on risk. We also considered the potential modulation of those associations by polymorphisms in GSTM1 and GSTT1.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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65 y old). After receiving informed consent, cases and controls were interviewed in person regarding known and suspected breast cancer risk factors; all data were self-reported. The Institutional Review Board of the State University of New York at Buffalo reviewed and approved the protocol for this study. Dietary assessment. An extensive, validated FFQ (12) was administered by the interviewer. Participants were asked about usual intake of 170 foods during the year 2 y before the diagnosis for cases and before the interview for controls. Portion size, using food models, and intake frequency were assessed to estimate grams of intake, and separate questions were asked for raw vs. cooked vegetables. Self-reported cruciferous vegetable intake was calculated as the sum of grams of intake (portion size x frequency) per month of broccoli, cabbage, sauerkraut, coleslaw, cauliflower, and brussels sprouts.
Laboratory analysis.
At the conclusion of the interview, permission was requested for a subsequent blood collection; 
54% of the women provided blood samples. DNA was extracted from blood clots (14), and PCR was used to determine the polymorphic GSTT1 and GSTM1 genotypes, i.e., presence or absence of the allele. GSTM1 and GSTT1 genotypes were determined by PCR restriction fragment length polymorphism as previously described, with multiplexing of GSTM1 and GSTT1, using CYP1A1 as an internal control to confirm amplification (15–17), and with 10% duplicates included. GST genotypes were classified as either null (i.e., homozygous deletion) or present (i.e., heterozygous or homozygous for the presence of each gene).
Data analysis.
Women were considered postmenopausal if they were <50 y old and had self-reported natural menopause, bilateral oophrectomy, or irradiation of the ovaries. For women 50 y old, menopausal status was assigned on the basis of self-reported cessation of menstruation, except for women taking hormone replacement therapy, who were classified as postmenopausal regardless of whether their menstrual periods had stopped. Reported BMI 2 y before the reference date was calculated as weight divided by the square of height (kg/m2), and was included as a continuous variable. Age at menarche, age at first pregnancy, and age at menopause were all treated as continuous variables. Family history of breast cancer (yes/no) was dichotomized. Broccoli and total cruciferous vegetable intake was categorized into quartiles based on distribution in controls, and was calculated separately for pre- and postmenopausal women due to differences in consumption patterns.
Because risk factors may differ between pre- and postmenopausal women (14,18), all analyses were conducted separately by menopausal status. Student’s t tests were utilized to determine mean case-control differences in lifestyle and reproductive factors. Odds ratios (OR) and 95% CIs were calculated from unconditional logistic regression models, using SPSSWIN version 11.0 statistical package (SPSS). ORs evaluating associations between cruciferous vegetable intake and breast cancer risk were adjusted in multivariate models for age, education, and standard breast cancer risk factors (age at menarche, age at first pregnancy, BMI, family history of breast cancer, and age at menopause for postmenopausal women). Modification of risk by GSTT1 and GSTM1 genotype was evaluated by calculating adjusted ORs for cruciferous vegetable intake and breast cancer risk within categories (allele present or absent) of genotypes. Associations with an 
-level < 0.05 were considered significant.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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50 y old, respectively) (personal communication, Carlos Crespo, Ph.D., Department of Social and Preventive Medicine, University at Buffalo, Buffalo, NY).
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As previously reported for GSTM1 (15,17), the GSTM1 and GSTT1 null genotypes were not associated with breast cancer risk in either pre- or postmenopausal women (data not shown). When associations were evaluated by GSTT1 genotype, inverse associations with broccoli consumption tended to be greater among premenopausal women with null genotypes (3rd tertile OR = 0.3, 0.1–1.6), than among those with present alleles [OR = 0.7 (0.3–1.8); Table 3]. There were no inverse associations among postmenopausal women. In fact, there tended to be an increase in risk among those with null GSTT1 with the highest reported intake of broccoli, although these risk relationships were not significant (P = 0.55) and the CIs were wide. For GSTM1, contrary to our hypothesis and findings for GSTT1 among premenopausal women, inverse associations were evident only among women with present alleles although, again, associations were not significant (P = 0.63). Among postmenopausal women, inverse associations with high consumption were noted among those with null GSTM1, but not GSTM1 present genotypes, as hypothesized.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Much of the focus in the past on compounds in cruciferous vegetables that could reduce risk of breast cancer has been on indole-3-carbinol. Michnovicz and Bradlow (19) and others hypothesized that indole-3-carbinol has antiestrogenic effects, primarily through induction of 2-hydroxylation of estradiol, resulting in nonestrogenic metabolites. Indole-3-carbinol can bind to the estrogen receptor with low affinity (20), which exerts antiestrogenic activities, represses 17ß-estradiol activated ER signaling, and downregulates the expression of estrogen-responsive genes (21).
Isothiocyanates, formed from glucosinolates in cruciferous vegetables, could also be responsible for inverse associations between cruciferous vegetable consumption and breast cancer risk. The chemopreventive effect of ITCs observed in animal models is likely due in part to their indirect effects on metabolism of xenobiotics, through inhibition of phase I activating enzymes (e.g., cytochrome P450), and induction of phase II detoxifying enzymes (e.g., GSTs) (6). Through this mechanism, increased induction of phase II enzymes could lead to quicker and more extensive excretion of reactive intermediates, whether their source is chemical carcinogens, reactive oxygen species, or hormone metabolites that are substrates for GSTs. ITCs are also substrates for metabolism by GSTs, and it was reported (22) that GSTM1 converts sulforaphane to the GSH conjugate and subsequent excretion. Based on the hypothesis that GSTM1 can metabolize ITCs, particularly sulforaphane, and abrogate their chemopreventive effects, studies were conducted to investigate interactions between GST genotypes, cruciferous vegetable intake or urinary ITCs, and risk of cancer and adenomatous polyps. Lin et al. (7) first evaluated this hypothesis, finding inverse associations between broccoli consumption and risk of colorectal adenomas, which were attributed to those with GSTM1 null genotypes. This was not found in relation to colon cancer, however (11).
Associations were also investigated in relation to lung cancer risk for which carcinogen exposure is a known risk factor, and the detoxifying effects of the GSTs may play a more important role. London and colleagues (8) found that individuals with detectable urinary isothiocyanates were at decreased risk of lung cancer, and risk was lowest among those who carried deletions in GSTM1 and GSTT1. Spitz et al. (9) found that risk was greatest among those with GST null genotypes who were low consumers of ITCs. Among higher consumers of ITCs, risk was greater for those with null alleles than those with present genotypes. These data argue that the inducing effects of ITCs on GSTs may be more important than their role in the metabolism and excretion of the chemopreventive agents. Among nonsmoking women in China, however, the strongest inverse associations with ITC intake on lung cancer risk were among those with GSTM1 and GSTT1 null genotypes (10). Inconsistencies between studies, the majority of which had adequate sample size and were well designed, could be attributed to study design issues, or to chance. However, GST genotypes encode for enzymes that are highly inducible by numerous exposures and processes, and that participate in extremely complex pathways. Thus, associations for 1 cancer site may vary from those for another; other exposures that are also substrates for GSTs and the weight of those exposures in cancer risk may ultimately determine the effects of GST genotypes on relationships between cruciferous vegetable intake and cancer risk.
Associations between breast cancer, cruciferous vegetable intake, and GST genotypes may be even more complex because of the strong role of estrogens in breast cancer etiology. A recent case-control study (23) evaluated associations between urinary ITCs and breast cancer risk, finding inverse associations among pre- and postmenopausal women, with the greatest inverse associations among those with deletions in GSTM1 and GSTT1, although relations were not significant. However, this study relied on a one-time measure of excreted ITCs, collected from women after a diagnosis of breast cancer. The validity and reliability of a single measure of prediagnostic levels are not clear. Habitual consumption of cruciferous vegetables before diagnosis was not associated with decreased breast cancer risk, although urinary ITC levels were validated against a FFQ (24). In contrast, when we assessed usual diet 2 y before the interview, we found that cruciferous vegetable intake, particularly broccoli, was associated with a decreased risk of premenopausal breast cancer. For diseases with long latencies, such as cancer, estimation of usual diet by FFQ more accurately reflects long-term exposure to dietary components. Although there is likely some degree of misclassification of consumption using FFQs, and the most important time period within which diet would affect risk is not known, questionnaire assessment may be more appropriate than use of a biomarker that reflects exposure in only the last 2–3 d.
In summary, our findings and those from other recent studies, suggest that specific vegetables, such as those from the Brassica family, may have important effects on breast cancer risk. These data support a rationale for public health efforts to encourage individuals to maintain diets high in vegetables, which are sources of numerous anticarcinogenic compounds.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Manuscript received 12 December 2003. Initial review completed 4 January 2004. Revision accepted 5 February 2004.
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LITERATURE CITED |
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