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Breast cancer is the most common cancer of women living in Western populations [92]. The incidence of disease and death from breast cancers in the US and Western Europe substantially exceeds rates observed in most of Southeast Asia [93-95]. Incidence and mortality rates of breast cancer in Chinese and Japanese women in Asia are reported to be significantly lower than those of Chinese and Japanese women living in the US. The age-adjusted death rates from breast cancer are 2- to 8-fold lower in Asian countries than in the US and Western Europe [96]. This difference in breast cancer incidence has been correlated with differences in dietary patterns [93]. A large body of literature, including epidemiological, human, animal, and in vitro data, supports a beneficial role for dietary estrogens, particularly as a protective agent against breast cancer. Migration studies have indicated that the differences in these rates are dissipated after one generation following emigration from Southeastern Asia to the US [97]. Breast cancer rates of North American-born Japanese and "early" Japanese immigrants are almost identical to those of Caucasian North Americans, whereas "late" immigrants have an incidence rate intermediate between the former groups and that of Japanese residing in Japan [97]. Such findings support the role for environmental conditions in the etiology of breast cancer. Hirayama [98] reported a significant graded inverse association in Japanese women between risk of breast cancer and consumption of miso (soybean paste soup). A diet high in soy products conferred a low risk of breast cancer in premenopausal women in Singapore [67]. Wu et al. [99] have report that the risk of breast cancer was lowered in association with the number of servings of tofu consumed per week. A review of existing epidemiological data on the role of soy in the risk of cancer revealed some evidence of a preventive effect [64].

Genistein has been the phytoestrogen of great interest in the reduction of breast cancer risk because it has been shown to exert both proliferative (estro-genic) and anti-proliferative (anti-estrogenic) effects in human cell lines [68, 100]. In the human ER-positive MCF-7 breast cancer cell line, these effects are biphasic and concentration-dependent with stimulation of cell growth occurring at low concentration of genistein (10-5 to 10-8 M) and dose-dependent inhibition at higher concentrations (10-4 to 10-5 M) [68, 75, 84, 100-108]. Sathyamoorthy et al. [100] have demonstrated a similar stimulatory effect with daidzein, equol and enterolactone at 10-6 M concentrations. The anti-prolifera-tive effects of genistein described above occurred in both ER-positive and ERnegative cell lines and thus appear not to be mediated by the ER activity alone [68]. Extrapolation of cell culture studies to humans is questionable, especially in terms of tumor growth inhibition. A high soy diet results in an approximate plasma level of 1-5 |M of genistein [40,109],whereas the studies describing an anti-proliferative effect indicate a minimum cell culture concentration of 10100 |M of genistein [64, 70]. Dees et al. [110] demonstrated that dietary estrogens at low concentrations do not act as anti-estrogens, but stimulate human breast cancer cells to enter the cell cycle. This paradoxical role of the growth-promoting effects of genistein on ER-positive breast cancer cells in vitro and the apparent preventive and tumor growth-inhibitory actions of genistein in vivo maybe most plausibly explained by genistein's ability to mediates its action via ER as an estrogen agonist while also cross-talking with other ER-independent cellular mechanisms at higher concentration to inhibit cell proliferation induced by genistein through ER pathways. Collectively, these data support the hypothesis that the actions of genistein on ER and on inhibition of cell proliferation are a result of distinctly different cellular mechanisms.

Isoflavones have been shown to exhibit anti-carcinogenic activity in vivo. Laboratory animals fed soy-fortified diets have demonstrated protective effects as measured by a decrease in breast tumor proliferation, tumor number, incidence, metastases and an increase in latency, after stimulation with direct-acting, e.g., N-methyl-N-nitrosourea (NMU) and indirect-acting, e.g., dimethyl-benz[a]anthracene (DMBA) tumor-inducing agents [111-113]. In addition, pre-pubertal genistein-treated rats developed fewer mammary gland terminal end buds, with significantly fewer cells in the S-phase of the cell cycle, and more lobules than controls at 50 days of age [114]. Interestingly, emerging evidence from animal studies suggests that short-term exposure to dietary isoflavones neonatally or pre-pubertally decreases carcinogen-induced differentiated cells in the mammary gland [114]. These studies support a concept derived from other epidemiological investigations that the protective effect of the Asian diet occurs early in life [115]. Perhaps the early administration of genistein resulted in a more mature gland with less-susceptible structures to later initiation by the chemical carcinogen [111,112]. This may explain why the epidemiological studies, which in essence focus on the adult consumption of soy, are relatively unimpressive. Recently, Yan et al. [116] investigated the effect of dietary supplementation of flaxseed, the richest source of lignans, on experimental metastasis of murine melanoma cells in C57BL/6 mice. The median number of tumors in mice fed the flaxseed-supplemented diets were not only lower than that of the controls, but the addition of flaxseed to the diet also caused a dose-dependent decrease in the tumor cross-sectional area and the tumor volume. These results provide experimental evidence that flaxseed reduces metastasis and inhibits the growth of the metastatic secondary tumors in animals. Dietary supplementation of soybeans, a rich source of isoflavone phytoestrogens, was also able to reduce experimental metastasis of melanoma cells in mice [117]. From these results, it has been suggested that flaxseed and soybeans may be a useful nutritional adjuvant to prevent metastasis in cancer patients.

Human data regarding phytoestrogens and breast cancer are limited. Two early prospective investigations on breast cancer were the studies in Hawaii by Nomura et al. [118] and by Hirayama in Japan [98]. Both studies found that the fermented soybean paste, miso, appeared to have a protective effect against breast cancer in premenopausal women. Using a case-control study design, Lee et al. [67] reported a significantly lower risk of breast cancer in premenopausal Chinese women in Singapore who consumed soy. Many studies thus far have attempted to correlate an increase in consumption of dietary estrogens with a decrease in breast cancer risk by measuring urinary excretion of phytoestrogens. Maskarinec et al. [119] conducted a cross-sectional study to investigate the associations between urinary isoflavone excretion and self-reported soy intake of 102 women of Caucasian, Native Hawaiian, Chinese, Japanese and Filipino ancestry. Japanese women excreted more daidzein, genistein, and glycitein than did Caucasian women, whereas Caucasian women excreted slightly more coumestrol than any other group. Equol was excreted at the highest rate by Chinese women, whereas all other women excreted equol at a very low rate. These results demonstrate differential intestinal absorption by ethnic groups. Dietary soy protein and isoflavone intakes during the previous 24 h were positively related to urinary isoflavone excretion. The strong correlation between urinary isoflavone excretion and self-reported soy intake validates the dietary history questionnaire which can now be used in studies exploring dietary risk factors for breast cancer. A study from California [44] has also reported urinary isoflavone excretion by ethnic group. In this study, no statistically significant difference among various ethnic groups for isoflavone excretion was found, but the small group of Japanese women (n = 5) excreted slightly more isoflavones than did other ethnic groups. Their results also showed that Japanese women excreted very low levels of coumestrol compared with Caucasian women. Ingram et al. [120] conducted a case-control study to assess the association between phytoestrogen intake (as measured by urinary excretion) and the risk of breast cancer. Women with newly diagnosed early breast cancer and controls had their urine analyzed for the isoflavone phytoestrogens daidzein, genistein and equol, and for the lignans enterodiol, enterolactone and matairesinol. After adjustment for age at menarche, parity, alcohol intake, and total fat intake, high excretion of both equol and enterolactone was associated with a substantial reduction in breast cancer risk.

Currently, there are no reported toxic effects in humans from eating soy protein. Asian women, who for centuries have consumed soy as a staple of the diet, have not experienced any evident adverse effects on their hormonal and reproductive systems. It remains to be determined if dietary estrogens are beneficial or, as suggested by some in vitro studies, constitute an additional carcinogenic risk factor for tissues where proliferation is controlled by estrogens. If the amount of estrogens that can be derived from the dietary sources does not contribute a level high enough to suppress ER-positive cell growth, dietary estrogens may increase the risk of breast cancer. The molecular effects of dietary-derived estrogen on the ER-positive breast cancer cells appear to be complex. The effects of dietary estrogens may be concentration-dependent and may interact with synthetic and natural estrogens. It may be premature at this time to suggest dietary changes that significantly alter the amount of dietary-derived estrogens until additional research can fully elucidate the effects they have on the reproductive tissues in terms of dose, tissue-specific effects, and potential interaction with other estrogenic compounds.

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