Much of the work in animal models has involved breast cancer, and because of the number of studies, the present discussion of animal models is limited to this condition as an example of the animal work. In a review of the literature, Barnes45 concluded that in two thirds of studies on the effect of genistein-containing soy materials in animal models of cancer, the risk of cancer (incidence, latency, or tumor number) was significantly reduced.45 Thus, in a study in which the growth and metastasis of the ER-negative human breast cancer cells MDA MB 435 were investigated using the athymic immunodeficient mouse model,46 flaxseed feeding resulted in significant reductions in established tumor growth rate of these ERnegative cells and a 45% reduction in total incidence of metastasis. Reductions in cell proliferation and expression of insulin-like growth factor-1 and epidermal growth factor receptor were observed on flaxseed feeding, suggesting that the effect of flaxseed was to some extent the result of downregulation of these growth factors. The concentration of vascular endothelial growth factor (VEGF) in the extracellular fluid was lower in the tumors. VEGF is a known stimulator of angiogenesis.47 Hence, the study suggested that the slower tumor growth rate and lower metastasis caused by flaxseed may be attributed to its effect on tumor growth and the inhibition of growth of the tumor blood supply.445
On the other hand when ER-positive human breast cells were implanted in ovariectomized athymic mice, the tumors were larger in the genistein-treated group than in the negatively treated group. The results showed that genistein can act as an estrogen agonist in the total absence of estrogen. The relevance of this in the human situation when detectable estrogen levels are present is uncertain. However, with detectable levels of circulating estrogen, it remains likely that there would be inhibition of cell growth due to blocking by flavonoids of the action of endogenous (mammalian) estrogen.48
In rats, studies by Thompson have indicated that feeding 5% flaxseed during the preinitiation stage, using the chemical carcinogen DMBA (i.e., 4 weeks before DMBA injection) or in the early promotion stage of carcinogenesis (20 weeks after DMBA injection), resulted in a 21 to 32% reduction in tumor incidence. When the lignans were tested separately from flaxseed, the lignans, secoisolar-iciresinol diglycoside (SDG), resulted in a 46% reduction in the number of tumors per rat.4
The effects on tumor inhibition may be related to the action of phytoestrogens in breast development. A reduction in the number of highly proliferative terminal end bud (TEB) structures in the developing mammary gland through differentiation to the less proliferative alveolar buds and lobules has been suggested to be protective against mammary cancer. Exposure to 5 to 10% flaxseed during gestation and suckling or throughout life significantly reduced TEB density in the mammary gland, whereas exposure after weaning had no effect. When the experiment was repeated with rats exposed to flaxseed only during gestation or gestation to postnatal day 50, the data indicated that the critical period for enhancing the mammary gland differentiation was during suckling. The flaxseed and SDG diets reduced the tumor incidence by 31.3 and 42%, respectively, total tumor load by 50.8 and 62.5%, respectively, and mean tumor size by 43.9 and 67.7%, respectively. These findings supported the hypothesis that exposure to flaxseed during an early stage of mammary gland development (i.e., suckling) can enhance mammary gland differentiation. In turn, this development of the glandular tissue may reduce the risk of breast cancer in adulthood, an effect that may be mediated by lignans.4
The IARC data for cancer incidence in 1990 and 2002 are of interest in relation to the links among diet, isoflavones and lignans, and cancer.4950 Data are presented from U.S. and U.K. to contrast to traditionally high-soy-eating parts of the world, Japan and China. Recognizing that traditional habits are changing in Asia, especially Japan, a further contrast is the comparison of findings from Japan and China. These data are presented on the understanding that the China data are likely to be less robust than those of the other three nations. The most significant finding was the rise in colon cancer in Japan, which now leads the world in both gastric and colon cancer incidence (Figure 15.2). This is of particular concern since epidemiologically the incidence of colon cancer has usually been related inversely with that of stomach cancer. Furthermore, the relative lack of increase in all cancers in China contrasts to the sharp rise of cancers in Japan, which in most instances shows a similar percentage increase to that seen in the U.S. and U.K. For Japan, it might be argued that these changes are due to the increased caloric consumption associated with rising height and increasing bodyweight, but it may also be related to the increased consumption of a more Westernized diet with reduced soy consumption and therefore lower isoflavone intake.
Adlercreutz20 in a review of the literature concluded that there was no convincing evidence to suggest that soy or isoflavone consumption during adult life was protective against breast cancer for women living in Western countries. However, moderate lifelong intake of soy products or isoflavone supplements may have beneficial effects on the cardiovascular system and bone metabolism, but negative effects on the breast could not be completely excluded, although equally positive findings are also present in the literature.20 The epidemiological data indicate that in the context of a healthy lifestyle soy consumption does not preclude low levels of breast cancer incidence. Furthermore, affluence and Westernization, in the absence of increased soy consumption seem to be the major drivers for increases in breast cancer. For other cancers such as prostate, and possibly colon and stomach, soy may well turn out to have beneficial effects. The alarming rise in colon cancer in Japan at a time of increasing Westernization perhaps hints that traditional Japanese habits, which include soy consumption, may be protective. However, there are no long-term, randomized, controlled trials of isoflavone or lignan consumption on cancer incidence or surrogate markers, such as aberrant crypt foci or polyps in the case of colon cancer. Future recommendations must be based on trial experience. In the absence of these there seems no reason to cease recommending to the public to eat more whole grains, seeds, and legumes, foods high in lignans and isoflavones.
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