Class Act: Soy and Breast Cancer – What’s the Connection?

November 26, 2008

soy.jpgCommentary by Alexis Melnick, NYU School of Medcine Class of 2009

Faculty peer reviewed

With the increasing popularity of soy foods in the American diet, there has been considerable debate over the link between soy and the risk of cancer, particularly cancer of the breast. The interest in this association stems from soy-containing isoflavones, soybean-derived compounds with chemical structures similar to estrogens that act as weak partial agonists at estrogen receptors. Initial data supported the chemopreventive potential of soy and were based on several findings: the historically low breast cancer rates in Asia, where soy foods comprise a significant proportion of the diet; other epidemiologic data demonstrating an inverse association between soy intake and breast cancer risk; and basic science research supporting the anti-estrogenic effects of isoflavones. In 1990, the U.S. National Cancer Institute concluded that soybeans contain several cancer-reducing agents; this led to an increase in the consumption of soy products by health-conscious Americans [1]. Several large food companies began marketing a variety of soy products, and in 2000 roughly 27% of U.S. consumers reported using soy products at least once per week, nearly double the 1998 figure [2]. However, there are persistent concerns that isoflavones may actually stimulate the growth of existing estrogen-sensitive breast tumors. In 2006, the American Cancer Society concluded that breast cancer patients may safely consume up to three servings of soy foods per day, but recommended against the use of more concentrated sources of isoflavones such as powders and supplements [3]. Other experts support total abstinence from soy products for breast cancer survivors and women at high risk. These recommendations have caused considerable confusion for women regarding both the primary and secondary preventive effects of soy on breast cancer.

Clinical studies, while few, appear to support a statistically significant risk reduction in breast cancer among women exposed to soy, particularly among women consuming high levels of soy during adolescence. A case-control study in China demonstrated that soy intake between 13 and 15 years of age was inversely associated with the risk of pre- and post-menopausal breast cancer [4]. A subsequent 2002 case-control study investigating both adolescent and adult soy intake found the greatest risk reduction in breast cancer among those who consumed high levels of soy during both time periods, and intermediate risk reduction among those with high intake during adolescence but low intake during adulthood [5]. Such results suggest that there may be a period of sensitivity during adolescence during which the developing breast is highly susceptible to environmental stimuli, including soy consumption. Several studies have also demonstrated dose-response relationships between soy intake and a reduction in breast cancer risk, while others have shown the strongest risk reduction for estrogen- and progesterone-receptor-positive breast cancer. A 2006 meta-analysis which summarized the results of 18 epidemiologic studies (including those mentioned above) of soy intake and breast cancer risk found a moderate association between high soy intake and reduced breast cancer risk among all women. In the 10 studies that stratified by menopausal status, the association between soy exposure and decreased breast cancer risk was slightly stronger in premenopausal than in postmenopausal women. Of note, the degree of exposure to soy, and the types of soy (fermented, nonfermented, isolated soy protein, and direct isoflavones) were highly variable among these study populations. Such heterogeneity limits our ability to interpret the findings of these studies [6].
In terms of secondary prevention, clinical studies of isoflavones also point away from an increased risk of breast cancer in breast cancer survivors. An analysis of four trials involving breast cancer patients, healthy subjects, and women undergoing breast biopsies or surgery for breast cancer, in which breast biopsies were taken before and after exposure to isoflavone supplements or isolated soy protein, show no increase in breast epithelial cell proliferation after the intervention [7]. This is in stark contrast to postmenopausal hormone replacement therapy which causes definite increases in breast cell proliferation [12]. Additionally, two other studies involving breast cancer patients failed to find an effect of isoflavone supplements on breast cell proliferation [7], giving clinical support to rodent evidence that the estrogenic effects of isolated soy protein and isolated isoflavones are virtually equal.

There are several mechanisms by which soy has been postulated to reduce breast cancer risk. Genistein, one of the three soybean isoflavones, has several anti-carcinogenic effects such as inhibition of epidermal growth factor receptor tyrosine kinase activity, inhibition of topoisomerase II activity, induction of apoptosis, and arrest of cell cycle progression. However, genistein has also been shown to cause proliferation of breast cancer cells in vitro, inhibit the effectiveness of tamoxifen, (a selective estrogen-receptor modulator used for breast cancer prophylaxis), and stimulate estrogen-receptor-positive breast cancer in rats and estrogen-receptor human xenoplants in athymic, ovariectomized mice [7,8,9]. These studies have several limitations. Breast cancer in athymic, ovariectomized mice may not be an accurate model for conditions in pre- or postmenopausal women, in which immune function is generally intact and levels of endogenous estrogen are not necessarily undetectable. Furthermore, more recent studies in mice with intact immune function have demonstrated that pretreatment with genistein actually enhances the immune system and is correlated with protection against mammary tumors [10]. Most studies utilized doses of genistein that greatly exceed typical dietary intake–at least 5 times the amount found in traditional Asian diets–and other studies used direct injection of purified isoflavones resulting in substantially higher levels of unconjugated isoflavones than those attained by dietary administration [7]. Lastly, with regard to the potential for genistein to block the effects of tamoxifen, other rodent models have shown enhanced efficacy of the drug in mice treated with isoflavones [11]. Clearly, more conclusive studies are needed.

The bottom line? There is little clinical evidence that soy promotes breast cancer, in women in general and in breast cancer survivors. On the contrary, published literature suggests that soy plays a role in the primary prevention of breast cancer and does not increase the risk of recurrence in breast cancer survivors. Certainly, more research is needed to elucidate precisely at what age and in what form these products can have their greatest risk-reducing effect. It appears that women may enjoy soy products without fear and should be assured that despite current controversy, the evidence for the benefits of soy greatly outweighs evidence for the risks.

Reviewed by Michelle McMacken MD, Assistant Professor of Medicine

References
1. Messina M, Barnes S. The role of soy products in reducing risk of cancer. J Natl Cancer Inst. 1991;83:541–46.
2. United Soybean Board. 7th Annual Consumer Attitudes about Nutrition, 2000-2001 National Report.
3. Doyle C, Kushi LH, Byers T, et al. Nutrition and physical activity during and after cancer treatment: an American Cancer Society guide for informed choices. CA Cancer J Clin. 2006:56:323-53.
4. Xiao OS, Fan J, Qi D, et al. Soyfood intake during adolescence and subsequent risk of breast cancer among Chinese women. Cancer Epidemiol Biomarkers Prev. 2001;10(5):483-8.
5. Wu AH, Wan P, Hankin, J, et al. Adolescent and adult soy intake and risk of breast cancer in Asian-Americans. Carcinogenesis. 2002;23(9):1491-6.
6. Trock BJ, Hilakivi-Clarke L, Clarke R. Meta-analysis of soy intake and breast cancer risk. J Natl Cancer Inst. 2006;98(7):459-71.
7. Messina MJ, Wood CE. Soy isoflavones, estrogen therapy, and breast cancer risk: analysis and commentary. Nutr J. 2008;7:17.
8. Ju YH, Fultz J, Allred KF et al. Effects of dietary daidzein and its metabolite, equol, at physiological concentrations on the growth of estrogen-dependent human breast cancer (MCF-7) tumors implanted in ovariectomized athymic mice. Carcinogenesis. 2006;27:856-63.
9. Ju YH, Doerge DR, Allred KF, et al. Dietary genistein negates the inhibitory effects of tamoxifen on growth of estrogen-dependent human breast cancer (MCF-7) cells implanted in athymic mice. Cancer Res. 2002;62:2474-77.
10. Guo TL, Chi RP, Hernandez DM, et al. Decreased 7,12-dimethylbenz[a]anthracene-induced carcinogenesis coincides with the induction of antitumor immunities in adult female B6C3F1 mice pretreated with genistein. Carcinogenesis. 2007;28:2560–66.
11. Mai Z, Blackburn GL, Zhou JR. Soy phytochemicals synergistically enhance the preventive effect of tamoxifen on the growth of estrogen-dependent human breast carcinoma in mice. Carcinogenesis. 2007;28:1217–23.
12. Conner P, Skoog L, Soderqvist G. Breast epithelial proliferation in postmenopausal women evaluated through fine-needle-aspiration cytology. Climacteric. 2001;4:7–12.
13. Hsieh CY, Santell RC, Haslam SZ, et al. Estrogenic effects of genistein on the growth of estrogen receptor-positive human breast cancer (MCF-7) cells in vitro and in vivo. Cancer Res. 1998;58:3833-38.

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