At present the aggregated results are still insufficient to permit final conclusions indicating that rye, whole grain or phytoestrogens are cancer-protective. There are, however, many in vitro and in vivo studies especially on prostate cancer, that point in that direction.

The presence of phytoestrogens (isoflavones) in Asian diets and the comparatively low rates of so-called Western diseases, suggest that these plant chemicals may have protective effects. Numerous studies have evaluated this hypothesis and it has resulted in an intense discussion about the relationships between phytoestrogens and cancer (Magee and Rowland, 2004). Most of the evidence regarding the effects of phytoestrogens in humans is epidemiological. The results of migration studies, as well as investigations on various dietary groups in the United States, Japan and Finland, suggest a protective role for phytoestrogens against the most common Western diseases (Adlercreutz and Mazur 1997, McCann et al. 2005a). The two major forms of cancer in the two sexes, breast and prostate cancer, vary considerably between countries, and migration studies clearly show that the western lifestyle has adverse effects on their incidence. The overall picture regarding cancer is, however, very complex.

Studies in animals:

In experiments with rats and nude mice, it has repeatedly been seen that rye bran and soy protein intake delay the early growth of hormone-sensitive prostate cancer. Rye bran and soy protein in the diet have been shown to delay the growth of transplanted hormone-sensitive prostate cancer in rats (Landström et al. 1998). Rye and soy diets markedly inhibit the prostate specific antigen (PSA) secretion of human LNCaP tumours transplanted to nude mice and these diets also increase tumour cell apoptosis (Bylund at al. 2000). In a study of Wikstöm et al. (2005), a rye bran diet increased epithelial apoptosis and reduced the epithelial cell fraction in TRAMP (transgenic adenocarcinoma of the mouse prostate)  tumours.

The active component(s) of the dietary complex of rye bran may be lignans, but other substances and/or mechanisms may be involved such as effects on insulin and IGF-1. Addition of fat to a rye diet abolishes the beneficial effects on tumour take, tumour cell apoptosis and tumour growth. Fat also decreased the urinary excretion of enterolactone, which show that fat interacts with the formation of enterolactone in the gut, possibly by means of a reduced rate of fermentation or absorption (Hallmans et al. 2003).

The observation that the cancer-protecting effects of components in traditional diets can be reduced just by adding fat may be of considerable importance for the understanding of the geographical and temporal changes in the incidence of prostate cancer. The experimental studies also show that the effect of diet is transient on prostate tumour growth and that no effect is seen on aggressively growing tumours. The results are, however, supported by the effects of purified extracts of lignans on experimental breast- and colorectal cancer found by Thompsons group in Canada, as well as by results using purified lignans in experimental prostate cancer in the study of Bylund et al. (2005).

Rye bran has been shown to slow down adenoma growth in two different animal models. Rye bran supplementation decreased the frequency of colon cancer in azoxymethane-treated rats (Davies et al. 1999), and rye bran was beneficial against intestinal tumorgenesis in multiple intestinal neoplasia (Min) mice (Mutanen et al. 2000). Hydroxymatairesinol, which has a structure close to matairesinol in rye, also showed anticarcinogenic effects in (Min) mice model (Oikarinen et al. 2000). The mechanisms for the possible protective effects are, however, not yet revealed.

In general, the relationship between lignans and cancer is far from clear, but according to the emerging view, the anti-cancer effects are more likely due to a concerted action of many types of phenolic compounds including lignans and isoflavonoids, than to individual substances. The inhibitory effect of soy protein and rye bran on experimental tumour growth may also be related to several other mechanisms.

Studies in humans:

Breast cancer:

Enterolactone is a biomarker for both the function of the intestinal microflora and the intake of lignan-rich food. In case control studies, except in that of Kilkkinen et al. (2004), a protective association has been observed between high enterolactone concentrations in blood (Pietinen et al. 1999) or urine (Ingram et al. 1997) and breast cancer while the results so far from prospective studies on breast cancer have been inconclusive (den Tonkelaar et al. 2001, Hultén et al. 2001). In three respective studies (Pietinen et al. 1999, Ingram et al. 1997, den Tonkelaar et al. 2001) a low level of enterolactone was associated with a high risk of breast cancer. In Hultén's study, a low plasma concentration of enterolactone was associated with an increased risk in all women after stratification on pre- and post-menopausal status. Surprisingly, in this population, high plasma concentrations of enterolactone were also associated with a tendency towards an increased breast cancer risk. In the study by Pietinen et al. (2001), the dietary studies showed that there was a significant positive association between plasma enterolactone and rye intake. Assuming that the hypothesis on the relationship between whole grain intake and breast cancer risk is true, it is not surprising that an association between enterolactone and breast cancer risk is not always found because in other populations the sources of lignans may be completely different. In the USA, the main sources of lignans have so far been coffee, orange juice and fruit (Horn-Ross et al. 2000), which are very different from the sources (whole grain cereals, vegetables and berries) in the Nordic countries.

Colorectal cancer:

There has long been strong support of the concept that dietary factors, such as dietary fibre-rich food, may protect against cancer, e.g. cancer of the colon and rectum (World Cancer Research Fund 1997). The concept of a protective effect of fruits, vegetables and whole grain cereals has been challenged, while no protective effect has been observed in some prospective studies using dietary questionnaires (Fuchs et al. 1999, Pietinen et al. 1999). No association has been detected between colorectal cancer risk and intake of plant sterols, with whole grain bread being an important source (Normén et al. 2001) or with enterolactone used as a biomarker for intake of dietary fibre-rich food (Lundin et al. 2001c).

However, support has been given in prospective studies to the protective effect that fibre-rich food has on colorectal cancer. In a study by Terry et al. (2001a), on a group of over 60,000 women, individuals with a very low intake of fruit and vegetables were at an increased risk. In a study of Larsson et al. (2005) whole grain consumption was shown to be associated with reduced colorectal cancer risk. In a large EPIC study the association between dietary fibre intake and incidence of colorectal cancer were examined in over 500 000 individuals. It was seen that in populations with low average intake of dietary fibre, an approximate doubling of total fibre intake from foods could reduce the risk of colorectal cancer by 40% (Bingham et al. 2003).

The conflicting findings emphasize the potential usefulness of intervention studies, the identification of critical phytochemicals with adverse or protective effects on cancer, or the identification of biomarkers of food intake. Intervention trials have not been conclusive or negative, and in one study using a purified fibre fraction, ispaghula fibre, the treatment was even associated with an increased recurrence of colorectal adenomas. Neither was a low-fat, high-fibre diet effective for preventing recurrence of colorectal adenoma in a large-scale intervention study (Schatzkin et al. 2001).

While so much evidence has been accumulated in support of the protective effect of fibre-rich food on colorectal cancer risk, follow-up studies on large prospective materials of colorectal cancers may be justified, using biomarkers fibre such as enterolactone for the dietary fibre complex, and perhaps, in the future, more specific biomarkers such as alkylresorcinols (for rye) (Chen et al. 2004) and avenanthramides (for oat).

Other cancers:

A number of prospective studies using enterolactone as a biomarker in blood are ongoing with regard to breast-, endometrial- and prostate cancer. The preliminary results of the first prostate cancer study have been presented. They were negative overall, with no clear associations observed (Stattin et al. 2002). However, very recent results from a study of Hedelin et al. (2006) support the hypothesis that consumption of certain foods high in phytoestrogens are associated with a lower risk of prostate cancer. Also the results from the study of McCann et al (2005b) support the hypothesis that phytoestrogen rich diet is important in reducing risks of hormone-related tumours.

For stomach cancer, including cardia, a large number of case control studies strongly suggest a protective effect (World Cancer Research fund 1997). The results are almost completely consistent with a protective effect associated with whole grain cereals. Further strong support comes from recent study on cardia cancer, performed on a population-based material (Terry et al. 2001b), where the protective association was strong for cardia cancer and somewhat weaker for adenocarcinomas of the lower oesophagus. Importantly, no indication of a protective effect was seen associated with oesophageal squamous cell carcinoma, which strongly supports the conclusion that recall bias has not been a significant bias-causing factor in this study. The most exciting mechanisms of a protection effect from whole grain cereals are connected with the binding properties of their N-nitroso compounds (Kurtz and Zhang 2001). Some preliminary data were presented by Jacobs at the Whole Grain and Human Health conference in Finland, in June 2001, based on the results of prospective studies. Surprisingly some results indicate a protective effect associated with the upper digestive tract and endometrial cancer.

A delay in clinical cancer onset may be very important from a public health perspective. Dietary intervention studies in humans, using various forms of endpoints such as apoptosis in tumours and changes in PSA concentration, are therefore required. Unfortunately, dietary intervention trials are costly and very time consuming. Nevertheless, they are needed in order to obtain final proof of the effects of diets.

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