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Symposium: Testing the Cruciferous Vegetable-Cancer Relationship: From Basic Science to Observational Studies and Back

Epidemiological evidence for chemopreventive effects of cruciferous vegetables on cancer risk.

Roswell Park Cancer Institute, Buffalo, NY

Abstract

SY18-03

Findings from studies of vegetable consumption and decreased cancer risk have been inconsistent. In additional to methodological issues, disparate findings may be due to the possibility that specific subgroups of vegetables are more strongly related to cancer risk, diluting the effects of total vegetable consumption. Based upon experimental data supporting a role for compounds found in cruciferous vegetables in carcinogenesis, such as precursors of isothiocyanates (ITCs), potential associations have been evaluated in relation to a number of cancer sites.

ITC metabolites are excreted in the urine, and cruciferous vegetable intake has been evaluated in two cohort studies of bladder cancer; in the Health Professionals' Study (HPFS) (1), cruciferae were the only vegetable group associated with decreased risk of bladder cancer, with the strongest associations noted for broccoli and cabbage. However, in the ATBC study (2), an intervention among male smokers, there were no associations between risk and intake. Somewhat consistent findings have been noted for prostate cancer. In one cohort and three case-control studies, including our own analysis in the Western New York Diet Study (3), associations were noted between higher intake and decreased risk (4–6), although other studies observed no effect (7, 8). In the HPFS, (9) a weak, non-significant inverse association between cruciferous vegetable intake and prostate cancer risk was observed, but inverse associations were strengthened when restricting analyses to men who received PSA screening tests.

For breast cancer, no associations were noted in the EPIC study (10), but in the Pooling Project (11), there were inverse, non-significant associations between risk and high intake of broccoli and brussels sprouts. These findings were replicated in a large case-control study in Sweden (12). We also found consumption of cruciferous vegetables, particularly broccoli, was marginally inversely associated with breast cancer risk in premenopausal women (13), and in the Shanghai Breast Cancer Study (14), urinary levels of ITCs were inversely associated with risk among both pre- and postmenopausal women.

ITCs are potent inhibitors of phase I, and inducers of phase II enzymes, such as glutathione S-transferases (GSTs). Through this mechanism, increased induction of Phase phase II enzymes could lead to quicker and more extensive excretion of reactive intermediates, such as chemical carcinogens. ITCs are also substrates for metabolism by GSTs. Thus, there has been an interest in potential interactions between cruciferous vegetable intake, GST polymorphisms, and cancer risk. Lin et al (15) noted that there were inverse associations between broccoli consumption and risk of colorectal adenomas, attributed to those with GSTM1 null genotypes, and in a colon cancer study (16), high consumers with GSTM1 null genotypes had a two-thirds reduction in risk, while GSTM1 present genotypes were associated with reduced risk regardless of diet. In a Chinese study, risk of colorectal cancer was also lowest among those with GSTM1 and GSTT1 null genotypes and high dietary ITCs (17).

The detoxifying effects of the GSTs may play an important role in lung cancer risk, where carcinogen exposure is a known risk factor. London and colleagues (18) found that individuals with detectable urinary ITCs were at decreased risk of lung cancer, and risk was lowest among those who carried deletions in GSTM1 and GSTT1. These associations were also observed in a large case-control study in Europe (19). Conversely, Spitz et al (20) 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. Similarly, in another large case-control study (21), higher cruciferous vegetable intake reduced lung cancer risk only among those with GSTM1 present genotypes. These latter results 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 non-smoking women in China, however, the strongest inverse associations with ITC intake on lung cancer risk were among those with GSTM1 and GSTT1 null genotypes (22). Inconsistencies between studies could be attributed to study design issues, or could be attributed to chance. However, it should be noted that GST genotypes encode for enzymes that are highly inducible by numerous exposures and processes, and participate in extremely complex pathways. Thus, associations for one cancer site may vary from those for another, and other exposures that are also substrates for GSTs may impact risk relationships. Nonetheless, the majority of these analyses support the concept that cruciferous vegetables may play an important role in cancer prevention, the strength of which may be dependent, to some extent, upon other carcinogenic exposures and genotypes for glutathione S-transferases.