Cancer And Phytoestrogens

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Phytoestrogens have been considered to have a preventive effect against various cancers. The consumption of phytoestrogen-rich foods such as soy, a source of isoflavones, and whole grain products, which contain lignans, is thought to play a role in the prevention of breast, prostate, and colon cancer. Other cancers also may be influenced by the presence of dietary phytoestrogens, but the studies in humans are comparatively few.

15.3.1 Breast Cancer

Early studies by Axelson and Setchell19 suggested that vegetarian women had a higher urinary secretion of lignans than omnivores. Later studies demonstrated lower urinary outputs of lignans in women diagnosed with breast cancer.19 The question arose whether these compounds exerted a tamoxifen-like action on breast cancer tissue related to low dose stimulation of the ER and higher dose blocking or whether other direct or indirect actions were responsible, such as increasing the concentration of serum hormone binding proteins.

Soy isoflavones may also reduce breast cancer risk by affecting endogenous sex hormone concentrations and prolonging the menstrual cycle. There is evidence from early studies in vitro and in vivo that suggests that phytoestrogens stimulate the production of sex hormone-binding globulin (SHBG) in liver cells.20 An increase in SHBG would lead to lower free-sex hormone concentrations. Longer menstrual cycles, which would lower breast cancer risk, have been seen in young women placed on soy experimentally. 21

The increased production of equol in the gut has been associated with a lower risk of breast cancer.20 Equol, known to be estrogenic, is a metabolite produced in vivo from the soy phytoestrogen, daidzein, by the action of gut microflora.22 Equol concentrations are high in people consuming diets rich in plant proteins, carbohydrates, and fiber, but low in those on a high-fat diet. High equol producers also have a slightly higher concentration of SHBG than low equol producers.

In a study to examine whether soy in the diet is related to mammographic parenchymal patterns, which have been shown to predict breast cancer, 406 women ages 45 to 74 were randomly selected from among 3421 women.23 These women were classified as displaying either high-risk (cases) or low-risk (controls) parenchymal patterns. Women with lower soy intake had higher percentage mam-mographic densities. The mammographically dense patterns, which are known to be associated with increased risk of breast cancer, are Tabar patterns IV and V.23 24 The Tabar IV pattern represents fibrous proliferation and the Tabar V pattern represents dense fibrosis. There was a reduction of these patterns with high intake of soy, which would be considered to be protective against breast cancer devel-opment.23 Ironically, a reduction in the risk of the Tabar IV and V patterns was also associated with high fat intakes. However, mammographic density can be reduced by an increase of fatty tissue in the breast as a result of a high-fat diet. In postmenopausal women, breast cancer risk increased linearly with increasing weight. Therefore the association of high body mass index (BMI) with increased risk may not be through increasingly dense mammographic patterns in postmenopausal women due to the increase of fatty tissue in the breast.23 High-risk patterns and high BMI, although both risk factors, are negatively confounding.24 Thus, the reduced occurrence of dense patterns with increasing age is consistent with the mammographically dense tissue being replaced by fatty tissue after menopause.23 In the Shanghai breast cancer study soyfood intake was associated with a decreased risk of breast cancer.25 The study included 1459 cases and 1556 age-matched controls. Women in Shanghai had levels of soy intake considered high; i.e., soy consumption was at least once a week. The women with the highest consumption had a 30% reduced risk of breast cancer with stronger reduction for ER-positive subjects compared to subjects who were ER negative. In this situation there was even greater reduction among women with a higher BMI. But perhaps the most protective effect of soy was found in the offspring of women who had significant soy intake during pregnancy.25 No association was found for women who increased their usual soy intake. It has been reasoned that women were required to eat soy at least once a week to maintain a constant level of isofla-vonoids in their body, as most isoflavonoids are excreted in the urine within 96 hours. There was no additional benefit seen with increasing soy intake among women who already took soy weekly.25

A further human study in Hiroshima and Nagasaki showed no significant association between reported consumption of soy and breast cancer risk.26 The 34,759 women in the Life Span Study cohort in Hiroshima and Nagasaki, who were alive at the time the atomic bombs were dropped and therefore exposed to radiation, completed dietary questionnaires in 1969-1970 or 1979-1981 and were followed until 1993. Among the 19 foods examined, the only statistically significant associations between breast cancer risk and diet were an increase in risk with increasing consumption of pickled vegetables and a decrease in risk with an increasing consumption of dried fish. These associations may be due to chance because of the large number of comparisons and because no plausible explanation can be given for pickled vegetables. There was no significant association between tofu or miso soup and reduction of breast cancer risk. The radiation exposure from the 1945 atomic bombs was a potential confounder of any association of soy consumption with breast cancer risk. However, it could be argued that this cohort would be more susceptible to breast cancer and thus act as a sensitive dietary indicator. All the analyses were adjusted for radiation exposure, and similar results were found in the subgroup of women exposed to very little radiation. It seems that even in potentially sensitive subjects soy consumption does not increase the risk of cancer.26

Finally, studies in the early 1990s noted a reduction in risk of breast cancer among premenopausal women with high soy intake in Singapore, with no relationship among postmenopausal women.27 28 Similar investigations in Japan and China found a significant association of a reduced risk with high tofu consumption in premenopausal women.2930 These human studies therefore suggest that soy consumption at least once a week prior to menopause had no adverse effect and possibly a protective effect on breast cancer.

15.3.2 Prostate Cancer

Two studies have been carried out to examine the effect of soy consumption with and without high levels of isoflavones to determine whether over a period of months prostate specific antigen (PSA) levels could be reduced. 31,32 No effect was observed in serum PSA levels either in the men with high starting levels of PSA or in those with low levels.33 More hopeful data were obtained by Kumar et al.33 They assessed the effect of a soy beverage containing 60 mg genistein vs. the control in 12-week studies in 76 men with prostate cancer and Gleeson score of 6 or below. PSA was reduced or unchanged in 69% of the test subjects compared to 55% in the placebo group. In this group mean starting PSA levels were in the 7.4 |jg/L range (total) with a free PSA of 0.99 to 1.03 |Jg/L.33 These data therefore support a possibly protective effect for soy in prostate cancer.

Reanalyses of the Seventh-day Adventist men provide some suggestion for this conclusion. The relationship between soy milk consumption and the risk of prostate cancer within this population was evaluated. This study involved 12,395 men and 225 incident cases of prostate cancer over a total of 15 years of observation. There was a 70% reduction in risk of prostate cancer in the men who drank soy milk several times a day. Total intake needed for a protective effect cannot be calculated due to the lack of information about exact portion sizes. Assuming a daily intake of 400 g of soy milk, then men who drank soy milk several times a day would have had a total isoflavone intake of approximately 7 mg daidzein and 10 mg genistein for a protective effect.34 An earlier cohort study including 7999 men with Japanese ancestry in Hawaii found that men who consumed tofu five or more times per week had a 65% reduction in cancer risk.35 However, no association was found with the other popular soy item, miso soup, and prostate cancer risk.35 It has also reported that a weekly intake of 160 mg of isoflavonoids in men prior to prostatectomy resulted in apoptosis of an adeno-carcinoma of the prostate, which is a similar effect to estrogen therapy.36 This further suggests a protective effect of isoflavones on prostate cancer and justifies additional study.

15.3.3 Other Cancers

The isoflavonoids have been found to have antiproliferative activity in two human intestinal tumor cell lines, Caco-2 and HT-29. Baicalein, genistein, bavachinin, and myricetin all increase apoptotic activity in the intestinal cell lines reaching significance for all four flavonoids in HT-29 but only for baicalein and myricetin in Caco-2 cells.37 This has led to the suggestion that flavonoids may reduce colon cancer risk by blocking hyperproliferation of the epithelium and by promoting apoptosis.38

At least one study has also indicated a protective effect of soy intake on gastric cancer.39 The study was a prospective study of a cohort of 30,304 men and women over 35 years old in Takayama, Japan. They were followed for 7 years during which time 121 deaths from stomach cancer occurred. A significant inverse relation was found between soy intake and stomach cancer in men with a relative risk for the highest vs. the lowest intake of soy of 0.50 (CI: 0.26 to 0.93) (P for trend = 0.030). Assessed separately, the women showed a similar effect but this did not reach significance.39 This study is of particular interest since it shows a protective effect of a traditional food, soy, despite a historically high level of gastric cancer in the region.

The consumption of soy foods has also been associated with a lower risk of endometrial cancer. An observational study including 832 women diagnosed with endometrial cancer aged 30 to 69 and 846 age-matched controls suggested a significantly lower risk of cancer with higher intakes of soy protein and fiber, but not significantly with higher intakes of soy isoflavones. The association of soy protein intake and endometrial cancer was also found to be similar for both pre-and postmenopausal women.40 More support for a protective effect came from a study of non-Asian women from California. It was found that higher intakes of phytoestrogens reduced the incidence of endometrial cancer.41 Two subject groups were assessed, the first consisted of 500 women aged 35 to 79 of African American, Latino, and Caucasian descent and the second consisted of 470 women age-and ethnicity-matched with 75% of all subjects postmenopausal. The endometrial cancer risk was significantly lower in the women with highest soy intake.41

It has been suggested that infant leukemia may be induced by exposure to DNA topoisomerase II inhibitors, which include flavonoids.42 Approximately 80% of infant leukemias have chromosome translocations involving the MLL gene. Patients with cancer treated with chemotherapeutic agents such as etoposide (VP16) or doxorubicin (Dox) can develop therapy-related leukemia. A proposed cause of infant leukemia includes maternal exposure to flavonoids. Maternal ingestion of flavonoids may induce damage at the MLL break point cluster region (BCR) of the DNA strand by inhibiting topoisomerase II and possibly leading to chromosomal translocations, which result in leukemia.42,43 Schroder-van der Elst et al.44 demonstrated that flavonoids do cross the placental barrier in a study where pregnant rats were injected with a radioactive flavonoid, which was found present in all fetal tissues.44 However, the exact significance of these findings remains uncertain and whether this also applies to other phenolics and lignans from fruit and vegetable consumption cannot be determined.

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