Bioflavonoids are associated with lowering the risk of chronic disease (artherosclerosis, cancer and inflammatory diseases). They are synthesized by plants and enter the human diet in vegetables and fruits. Epidemiologists have concluded that the diet is a large factor in the lower rates of breast and prostate cancer in Asians compared with Americans (1), a protection which is largely lost after one generation following immigration to the USA (2). Increased consumption of one dietary factor, soy (a rich source of the isoflavonoids, genistein, daidzein and glycitein), has been found to be associated with a reduction in chronic disease (see review in ref 3). A reduction in risk of breast cancer and prostate cancer associated with soy consumption has been observed in studies reported in both SE Asia (4) and the USA (5,6). In rat models of breast cancer, whole soy and some soy protein preparations were shown to inhibit the appearance of chemically-induced mammary tumors(7-9). Removal of the isoflavonous from soy by alcohol extraction eliminated the anti-cancer effect (9). The isoflavones are present in soy as beta-glucosides; these are hydrolyzed in the gut to release the aglucones - the latter have been shown to be the active forms in many in many in vitro systems. Administration of genistein (as its aglucone) to rats has been shown to be chemopreventive in model of breast cancer (10). When given in pharmacological does subcutaneously (s.c) in the neonatal (days 2-6) or the prepubertal (days 16-20) periods, the number of mammary tumors induced by the carcinogen dimethylbenzanthracene
(DMBA) was reduced by over 50% (11-15). As a better model of the exposure of humans to isoflavones, merely giving genistein in the diet to the dam during her pregnancy and maintaining it so the pups are exposed to genistein via the mother’s milk until day 21 of life (when they are weaned), provide a dose-dependent protection from mammary tumor formation (16). Morphological analysis revealed that genistein initially up-regulated the epidermal growth factor receptor (EGF-receptor) and stimulated mammary gland differentiation (17). This resulted in down-regulation of the EGF-receptor in adult mammary glands, an important risk parameter in recurrent breast cancer in women. In this respect, genistein exposure mimics the effect of an early first pregnancy, well known to lower breast risk. Exposure to genistein in later stages of life is not so protective - in a MNU model of breast cancer, the multiplicity of mammary tumors was 25-30%, even when given i.m? (18). In ovariectomized nude mice, inclusion of genistein in the diet increased the rate of a human MCF-7 breast cancer cell xenograft. In this case, genistein’s weak estrogen effects did not have to compete with physiologic estrogens. In rat models of prostate cancer, genistein and soy protein fractions have been shown to have weak chemopreventive effects. However, the models are not ideal. Most recently, investigator have begun using genetic models of breast (mutp53/Wnt-1) and prostate cancer(mut53) where susceptibility to tumor formation is so high that in some cases carcinogens are not needed at all. Early results from these models strongly support a chemopreventive role for dietary soy and genistein. Although genistein appears to have a role in chemoprevention as a weak estrogen, it has several other biological properties which may influence the risk of cancer. These include inhibition of protein tyrosine kinases, inhibition of pathways of inflammation, antioxidant effects, altered synthesis of certain growth factors, and inhibtion of metastasis and angiogenesis (see ref 19 for a summary of these mechanisms). At this time, systematic clinical studies in humans have not been reported (20). Existing data from clinical trials involving the use of soy and its isoflavones are conflicting - soy-induced changes in nipple aspirate fluid volume and the presence of atypical aplasia are parameters associated with increased cancer risk (21), whereas reduction in DNA oxidation is consistent with risk reduction(22). In summary, animal studies have revealed that exposure to isoflavones may produce a beneficial reduction in cancer risk - however, in both animals and humans the timing of exposure may prove to be critical.
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