The impact of soyfood intake on breast cancer risk has been intensely investigated. This focus can be attributed to soyfoods being uniquely rich dietary sources of isoflavones. Isoflavones are classified as both phytoestrogens and selective estrogen receptor (ER) modulators. The finding that dietary genistein, the primary soybean isoflavone, stimulates the growth of existing mammary tumors in ovariectomized athymic mice implanted with ER-positive breast cancer cells has led many oncologists to advise their patients against the use of soyfoods. However, the clinical evidence indicates that isoflavone exposure has little effect on markers of breast cancer risk. Furthermore, a pooled analysis that involved 9,514 breast cancer survivors found higher isoflavone intake was associated with a statistically significant 25% reduction in recurrence over the average 7.4-year follow-up period. Given the clinical and epidemiologic data, our position is that clinicians should allow soyfood use by patients for whom soyfoods already represent a normal part of their diet, and should not discourage other breast cancer survivors from moderate consumption.
The relationship between soyfood intake and breast cancer has been rigorously investigated for 2 decades. The presence of isoflavones in soyfoods, diphenolic molecules classified as phytoestrogens, primarily accounts for the interest in this relationship. Initial focus was on the possible breast cancer–protective properties of soyfoods; a result of the (1) low historical breast cancer incidence rates in soyfood-
consuming countries, (2) increased breast cancer incidence rates among Japanese immigrants to the United States, and (3) chemopreventive properties of isoflavones observed in vitro. Compelling yet speculative evidence suggests that soyfoods reduce breast cancer risk, but to derive this proposed benefit requires consumption during childhood and/or adolescence.
In recent years attention has turned to the possible role of isoflavones in stimulating the growth of estrogen-sensitive breast tumors, as has been demonstrated in a widely used ovariectomized athymic mouse model. As a result, clinicians generally advise breast cancer patients against regular soyfood consumption. A Canadian survey found that 25% of estrogen receptor (ER)-positive breast cancer patients stopped consuming soyfoods after receiving their diagnosis. This issue is of obvious public health importance. In the United States alone, of the estimated 13.7 million Americans currently alive with a history of cancer, 41% had received a diagnosis of breast cancer.
However, recently published clinical and prospective epidemiologic research questions the need for the advised restriction against soy. Also, doubts have been raised about the utility of the ovariectomized athymic mouse model for understanding the impact of isoflavones in humans. Furthermore, findings from the Women’s Health Initiative trials illustrate the uncertainty surrounding even the long-term use of estrogen, as opposed to combination hormone therapy, in the etiology of breast cancer. It is argued here that it is now time for oncologists and other clinicians to reconsider proscription against the use of soyfoods by women with a history of breast cancer.
Among commonly consumed foods, only soybean-derived products provide physiologically relevant amounts of isoflavones. The soybean contains 12 different isoflavone isomers: the three aglycones genistein (4',5,7-trihydroxyisoflavone), daidzein (4',7-dihydroxyisoflavone), and glycitein (7,4'-dihydroxy-6-methoxyisoflavone); their respective β-glycosides genistin, daidzin, and glycitin; and three β-glucosides each esterified with either malonic or acetic acid. (Isoflavone amounts used in this text refer to the aglycone equivalent weights.) When all forms of the individual isoflavones are considered, genistein, daidzein, and glycitein account for approximately 50%, 40%, and 10%, respectively, of the total soybean isoflavone content.
There are approximately 3.5 mg of isoflavones per gram of protein in traditional soyfoods, whereas in some more modern forms of soy as much as 80% of the isoflavone content is lost during processing. On average, there are 20–30 mg of isoflavones per serving of traditional soyfoods (eg, 250 mL soymilk, 100 g tofu), and older Japanese and Shanghai Chinese individuals consume about 30–50 mg of isoflavones per day.
Isoflavones have a chemical structure similar to estrogens, bind to ERs, and exert estrogen-like effects under certain experimental conditions. For these reasons, isoflavones have been classified as phytoestrogens despite their many other biological mechanisms of action. Genistein, which is the main circulating and best-studied isoflavone, transactivates ERα and induces estrogenic effects with 103–104 less potency than 17β-estradiol. However, serum isoflavone concentrations following a high-soy meal can reach low micromolar levels, thereby exceeding postmenopausal total estrogen levels by ~103.
In addition to being phytoestrogens, isoflavones are classified as selective ER modulators (SERMs). The effect of any given SERM on a specific tissue depends upon the conformational shape of the ligand-receptor complex, the ERα:ERβ ratio, and the types of co-activators and co-repressors in cells. The tissue selectivity of isoflavones likely derives from their preferential binding to and transactivation of ERβ in comparison with ERα. These two receptors have different tissue distributions and can have different functions. In the breast, activation of ERβ appears to inhibit the stimulatory and proliferative effects of ERα activation.
The physiological implications of the preferential binding of genistein that occurs at the molecular level at certain concentrations are not fully understood. Nevertheless, there are numerous clinical examples of isoflavones exerting effects similar to those of estrogen on some tissues without effects on other estrogen-sensitive endpoints, although there is very limited evidence demonstrating anti-estrogenic effects.[16-18]
Finally, as mentioned previously, isoflavones potentially exert physiological effects independent of ER binding as they, especially genistein, affect signal transduction pathways in vitro by inhibiting the activity of enzymes (eg, tyrosine protein kinase, mitogen-activated kinase, DNA topoisomerase, etc.) and regulating cellular factors that control the growth and differentiation of cells. The physiological relevance of many of these properties is unclear because the in vitro concentrations at which these effects are observed are generally far higher than can be achieved in vivo. Nevertheless, there is animal and clinical evidence of ER-independent effects of isoflavones.
Preclinical Effects of Genistein
Genistein exerts a biphasic effect on MCF-7 (an ER+ human breast cancer cell line) cell growth in vitro. At physiologically relevant concentrations, the estrogenic actions of genistein result in cell growth (in an estrogen-depleted media), whereas only at much higher concentrations do the ER-independent effects of genistein on signal transduction result in growth inhibition. Because the estrogenic effects of genistein are minimized in an estrogen-rich medium/environment, it has been proposed that isoflavones function as estrogen antagonists in premenopausal women and as estrogen agonists in postmenopausal women. However, this conceptual framework is probably not applicable to breast tissue. Although circulating estrogen levels in postmenopausal women are only one-third those of premenopausal women, breast tissue estrogen concentrations are similar in women regardless of their menopausal status[21,22] because of local estrogen synthesis and uptake from the circulation.
The in vitro stimulatory effects of genistein on MCF-7 cells were largely overlooked until this isoflavone was also found to stimulate the growth of mammary tumors in ovariectomized athymic mice implanted with these cells. It was subsequently shown that neither daidzein nor its metabolite equol has such effects and genistein is without effect on ER-negative breast cancer cells. In the basic model demonstrating stimulation, after tumors reach a cross-sectional area of ~30–40 mm2, the estrogen pellet, which is implanted to stimulate tumor growth, is removed, resulting in tumor regression in mice consuming a soy-free diet. In contrast, after an initial period of regression, tumor regrowth occurs in mice fed a soy-free diet that is supplemented with a variety of genistein/genistin-containing products.
Research from the above-described model also shows that genistein inhibits the efficacy of tamoxifen and letrozole, and that despite containing similar amounts of genistein/genistin, tumor growth is positively related to the degree to which the isoflavone-containing product has been processed. For example, soy flour (the least processed soyfood evaluated) does not stimulate tumor growth (although it does not allow regression to occur), whereas isolated genistein stimulates tumors to a greater extent than mixed isoflavones. This processing effect has helped garner support for the use of minimally processed soyfoods by breast cancer patients but has also led to strong warnings against the use of soy (isoflavone) supplements. However, this distinction among different genistein-containing products has not been tested clinically. Such investigations are warranted given that recent evidence indicates that the “processing effect” is not applicable to humans.
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