Phytoestrogens And Carcinogenesis

Almost all animals are exposed to an array of environmental chemicals, some of which can mimic the activities of endogenous hormones. Different plant products and synthetic compounds are known to have similar chemical compositions and act as estrogens.146 These estrogenlike compounds (so-called phytoestrogens), under laboratory conditions or in the natural environment, might be capable of causing a spectrum of adverse effects on the endocrine system that eventually cause several disorders, including tumorigenesis.147-150 Many in vitro studies using breast cancer cells indicate that phytoestrogens alone imitate the estrogenic effect and induce estrogen-dependent protein (pS2) and cell proliferation in ER-positive MCF-7 cells.146 However, in the presence of estrogen, the effect of phytoestrogens was reversed and the effect was not ER dependent.146 This issue remains a source of debate.151

Despite the adverse effects of naturally occurring phytoestrogens, these compounds also exhibit beneficial effects.146 Both epidemiological and experimental studies have shown that the consumption of phytoestrogen-rich diets may reduced the risk of cardiovascular diseases, menopausal disorder, osteoporosis, as well as breast and prostate cancers,146152-15 suggesting that their use may be worthwhile.155 There are two principal categories of phytoestrogens, isoflavones and lignanes. Isoflavones and flavones, represented by genistein, luteolin, and daidzein, are produced by leguminous plants (soybean, alfalfa), while lignanes are found in high concentration in linseed.146 The commonly available lignanes are enterolactone and enterodiol. These phytoestrogens have been reported to be weak estrogen-receptor agonists in the uterus and vagina of female rats.155 However, more genistein is bound to ERp than to ERa, so it could have an antiestrogen effect in systems with higher levels of ERp than ERa. It shows an inhibitory effect on estrogen-mediated endometrial carcinogenesis in mice, possibly by suppressing the estrogen-responsive genes, such as c-fos and c-jun and the internal cytokines IL-1a and TNFa.156

From the results of several independent studies, flavonoids could be considered valuable as anticancer therapeutic agents. With the use of soy phytoestrogens and the avoidance of hormonal replacement therapy (HRT), encouraging results have been obtained with breast cancer survivors. Furthermore, administration of phytoestrogens to postmenopausal women, along with the anti-estrogen tamoxifen, has provided encouraging results. Dietary phytophenols are now also considered to be anticarcinogenic. Tea, isoflavones, catechins, quercetin, resveratrol, and lignan are known to inhibit carcinogenesis by affecting estrogen-related activities.157-161 Consumption of soy milk substantially lowered serum estrogen levels, which was assumed to reduce breast cancer risk.146

Together, these studies indicate that the phytoestrogens exhibit a complex biphasic effect on the development of carcinogenesis. These compounds have both stimulatory and chemopreventive actions on mammary tumor cells. Although, the pathways of their actions are not clear, some researchers predict that timing of exposure will prove to play a critical role in determining the positive or negative actions of these compounds. The protective effect of genistein on chemically (DMBA) induced breast tumorigenesis is more pronounced when rats are exposed to it during the neonatal or prepubertal period compared with exposure during a later period of life, suggesting an important developmental effect.154162

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