Our finding that dietary phytoestrogens, both lignans and isoflavones, are associated with a reduction in colorectal cancer risk is important, because diet is potentially modifiable. Dietary intake resulting in classification within our top tertile of daily isoflavone or lignan intake is quite achievable. For example, daily isoflavone intake (>1.0 mg) could come from 1 small glass of soy milk or a small bowl of miso soup, and lignan intake (>0.26 mg) could come from 2 peaches, 1/2 slice of multigrain bread, or a pinch of flaxseed (9
). To our knowledge, no previous epidemiologic study has evaluated lignan intake, the phytoestrogen most prevalent in North American diets, in relation to colorectal cancer risk (6
). Epidemiologic studies have assessed isoflavone intake and cancer risk, with some reporting that increased soy product intake is associated with reduced colorectal cancer risk (17
Several epidemiologic studies conducted in Asia (19
) and 1 conducted in Hawaii (18
) evaluated the association between individual soy foods (main source of isoflavones) and colorectal cancer risk. Although some of these studies reported reduced colorectal cancer risk, particularly for nonfermented soy foods (e.g. tofu) (19
), lack of an association between tofu intake and colorectal cancer risk was also reported (26
), and occasionally findings differed by colorectal cancer sub-site, type of soy food, and sex (25
). The only case-control study in North America found that legumes and soy products (analyzed as 1 group) were associated with a reduction in colorectal cancer risk; however, tofu alone showed no association (18
The main limitations of previous studies were small sample size and the assessment of specific soy food intake rather than total phytoestrogen intake. None of these studies were designed to evaluate phytoestrogen intake; thus, evidence of an association is indirect. Findings from animal studies suggest phytoestrogens are associated with a reduction in colorectal cancer (13
). To our knowledge, our study is the first epidemiologic study to examine the association between colorectal cancer and lignans common in Western diets; recently available food composition data for lignans (secoisolariciresinol and matairesinol) were added to the analytic database applied to the FFQ.
Only recently have researchers modified FFQs and analytic databases such that total phytoestrogen (both isoflavone and lignan) intake can be measured in epidemiologic studies (6
). Historically, the lignan content of foods was not included in standard nutrient databases. Biomarkers of phytoestrogen intake have also been examined, and although promising (64
), have limited usefulness in a case-control studies where biologic specimens are obtained postdiagnosis.
It is thought that phytoestrogens may act via: 1
) hormonal effects mediated by ER binding; 2
) nonhormonal actions by altering processes involved in carcinogenesis such as apoptosis and antioxidant activity; or 3
) interaction with enzymes involved in sex steroid biosynthesis and metabolism (23
). Isoflavones may alter CYP(1A1,1A2,1B1)-mediated estradiol metabolism by reducing formation of carcinogenic hydroxylated metabolites (33
) while increasing less reactive 2-OH estrone and 16α-OH estrone metabolites (69
). Also, phytoestrogens may inhibit CYP-dependent estrogen metabolism by acting as competitive substrates, or they may reduce circulating levels of estradiol by induction of CYP enzymes (70
Much is known about the protective association between estrogens and colorectal cancer risk. Epidemiologic studies and trials consistently report a significant reduction in colorectal cancer risk among women who used HRT (20
). It has been suggested that estrogens may influence colorectal cancer risk by modification of lipids and bile acids thought to be involved in carcinogenesis (74
) or by reducing the likelihood of estrogen-receptor methylation (76
), because the ER gene is thought to play a tumor suppressor role (76
). English et al. (79
) report that estrone decreases colonic cell proliferation, whereas estradiol does not, suggesting the HRT-protective effect may be due to estrone and the metabolism of estrogens may also be important (74
Phytoestrogen metabolism is poorly understood (32
), although its large interindividual variation (13
) likely involves both mammalian enzymes and intestinal bacteria (33
). Phase I and II enzymes, important in metabolism of endogenous estrogens, may be important in phytoestrogen metabolism because of the structural similarities of these substrates and because they are abundant in the liver and small intestine where phytoestrogen metabolism occurs (33
). Isoflavones and lignans are metabolized by CYP(1A1/1A2/1B1,2E1), COMT, GST, and UGT enzymes and distinct variants acting on the same phytoestrogens produce different metabolites with varying bioactivities (32
). The role of intestinal microbes in phytoestrogen metabolism has also been demonstrated and variant bacterial species or strains may explain interindividual variation (82
Far more is known about the metabolism of endogenous estrogens. It is reasonable to assume that, given the structural similarity, phytoestrogens may be metabolized similarly to estrogens. Variation in estrogen metabolism affects the level of circulating estrogen metabolites. Most pathways of estradiol and estrone metabolism involve CYP enzymes (CYP1A1, CYP1A2, CYP1B1, and CYP3A4), which carry out irreversible hydroxylation (87
). COMT also plays an important role by converting hydroxylated estrone/estradiol into methoxy derivatives that are inactive estrogens (90
). These enzymes are polymorphic, with genetic variants exhibiting varying levels of enzyme activity/inducibility (91
Our evaluation of gene-environment interactions was of a hypothesis-generating nature. An improved understanding of interactions between phytoestrogen intake and genetic factors may provide insight into the mechanisms of carcinogenesis, as well as help in the development of colorectal cancer prevention strategies. Our data suggest the reduction in colorectal cancer risk associated with phytoestrogen intake is not markedly modified by polymorphisms in genes suspected of involvement in phytoestrogen metabolism (e.g. CYPs, COMT, GST, and UGTs genes).
Possible limitations of our study should be noted. Because fatal cases were excluded, survival bias may be a concern; if phytoestrogen intake affects survival, then our findings may be biased as cases with better survival are overrepresented. However, most colon cancer risk factors do not differ by stage of disease (100
). As both our cases and control subjects were selected from population-based sampling frames, selection bias is unlikely. Furthermore, many known risk factors (101
) were found to be associated with colorectal cancer risk in our dataset, suggesting the cases and controls are representative (40
). However, response bias is always a concern if high response rates are not achieved. Although unlikely, bias could have been introduced if participation was differential regarding both case and exposure status.
Possible confounding by known colorectal cancer risk factors was evaluated, and adjusted for, in our analyses. Because dietary fiber may be a confounder of the lignan and colorectal cancer risk association, dietary fiber was controlled for in the lignan analysis. Fruit and vegetable consumption was also evaluated as potential confounders but were not identified as confounders. It is possible that phytoestrogen-rich food intake may be a marker for other factors associated with colorectal cancer risk or may be associated with the intake of other protective food components. Although potential confounders were evaluated, residual or unknown confounding remains a possibility. It should be noted that whereas the Hawaii FFQ has been validated among a multi-ethnic American population (44
), it has never been validated among a Canadian population. Recall bias is always a concern in case-control studies, because cases may report exposures differently than controls; however, because information on a wealth of factors was collected in the epidemiologic questionnaire, it would be unlikely that participants would focus on our particular study hypothesis. Furthermore, the usual concern is that cases overreport the exposure of interest, but in this study, cases had a lower intake of phytoestrogens. It is unlikely that overreporting of phytoestrogen intake (misclassification) by the control subjects is responsible for the protective effect we observed.
Phytoestrogen intake is likely underestimated for some subjects, because the FFQ did not include all phytoestrogen-containing foods. Flaxseed, which contains a high concentration of lignans, is omitted, although this is not a frequently consumed food item. Soy milk, alfalfa sprouts, and mung bean sprouts, all of which contain isoflavones, were not captured by the FFQ. Future cancer studies should expand upon the standard FFQs available such that they include all important food sources of phytoestrogens. Many of these food items (e.g. flaxseed, flax bread, soy milk, sprouts) are not typically included in the common FFQs available for epidemiologic studies.