Soy Foods and Breast Cancer Risk Reduction
October 1999; Volume 2: 109-113
By Joya Tillem, MD and Mary Hardy, MD
Does eating soy confer a reduction in the risk of breast cancer? With mounting evidence that diet influences the risk of hormone-related cancers, it is natural to wonder if some dietary factor plays a role in breast cancer. Epidemiologic studies reveal a lower incidence and mortality in hormone-dependent cancers in Asian women and men who ingest a traditional Asian diet compared with their Western counterparts. Since traditional Asian diets are strikingly different from traditional Western diets, scientists hypothesize that soy might play a role in the prevention of breast cancer.
History and Common Usage
Soybean (Glycine max L.) is an annual legume of the Fabaceae family that likely originated in Asia. It has been cultivated extensively; the United States is the world’s principal producer. The soybean seed is up to 30% protein by weight. Commonly consumed soy foods include fresh, boiled, or steamed whole beans; soy milk, a whitish suspension of pressed beans; and tofu, a soft curd prepared from coagulated whey of soy milk. Soybean oil is commonly used in commercial food preparation. Miso (seasoned fermented soybean paste) and textured soy protein are increasingly available at the retail level.
Constituents
Soy products have recently become popularly known for containing phytoestrogens, which are plant-derived substances that bind to or activate the estrogen receptor. Phytoestrogens are present in most plants. Three major classes of phytoestrogens have been identified: isoflavonoids (genistein and daidzein); lignans (enterodiol, enterolactone, and matairesinol); and mycotoxins (zearalenone). Isoflavones, as the main phytoestrogens found in soy, have been reported to have antioxidant, antibacterial, and antiparasitic actions.1
Most of the 1,000 known isoflavones are from the Legurninosae family (legumes). Only four isoflavones maintain potent phytoestrogen activity—genistein, daidzein, biochanin, and formo-nonetin.
Mechanism of Action
Structurally, isoflavones are closely related to estrogenic steroids. In vitro and in vivo assays disclose isoflavones to be weak estrogens, binding to mammalian estrogen receptors.2 Similarly, in immature mice, isoflavones have been shown to induce uterine hypertrophy.3 In both cell-culture as well as animal experiments, phytoestrogens proved to be tumor inhibiting.2 The exact mechanism by which this process occurs has yet to be determined. However, isoflavonoid compounds stimulate synthesis of sex hormone binding globulin (SHBG)4 and may inhibit tumorigenesis by increasing SHBG levels, thereby reducing the accessibility of estrogens. Importantly, isoflavones possess strong antioxidant activity as well.5
In plants, phytoestrogens are present in glycoside form. The metabolism of phytoestrogens increases their biological potency. The hydrolysis of glucoside to aglucone occurs in the proximal colon by beta-glycosidase. Aglucone either undergoes fermentation by gut flora or conjugation in the liver. A proportion is excreted in bile and joins the enterohepatic circulation. The primary route of excretion is through the urine, with a half-life of less than 24 hours. This metabolic process results in an increase in phytoestrogen potency. For example, the methylated form of daidzein, formononetin, has 40 times more estrogen receptor binding affinity than daidzein.
| Table 1-Isoflavone content in commercially prepared soy foods | |||
| Genistein Per Serving* | Daidzein Per Serving* | Soy Food | Serving Size |
| Soy yogurt | 8 oz | 21 | 13 |
| Vegetable soy burger | 1 burger | 16 | 10 |
| Tempeh burger | 1 burger | 16 | 9 |
| Soy hot dogs | 2 hot dogs | 7 | 3 |
| Tofu vegetable pockets | 1 pocket | 6 | 1 |
| Soy or tempeh bacon | 3 slices | 4 | 2 |
| Tofu breakfast burrito | 1 burrito | 4 | 2 |
| Soy ice cream sandwiches | 1 sandwich | 3 | 4 |
| Tofu potpie | 8 oz | 2.6 | 1 |
| Tofu vegetable lasagna | 8 oz | 2.5 | 1 |
| Tofu enchilada | 4 oz | 1.4 | 1 |
| Macaroni and soy cheese | 8 oz | 1 | 0.5 |
| *mg/serving | |||
| Adapted from: Kirk P, et al. Development of a soy food frequency questionnaire to estimate isoflavone consumption in US adults. J Am Diet Assoc 1999;99:559. | |||
Of the 1,000 known isoflavones, which of the following maintain potent isoflavone activity?
a. Genistein
b. Daidzein
c. Biochanin
d. Formononetin
e. All of the above.
Clinical Trials
We conducted a systematic review of literature using MEDLINE, PubMed, the Internet, an alternative medicine literature CD-ROM, and the Cochrane database. Although there have been case-controlled studies, no prospective, randomized, placebo-controlled, double-blind studies have been published on the role of soy or isolated phytoestrogens in breast cancer prevention.
In 1991, Lee et al published a study on the effects of diet on breast cancer risk in Singapore using case-controlled retrospective methods.6 Two hundred women with a recent histologically confirmed diagnosis of breast cancer completed a quantitative food-frequency questionnaire to determine intake of selected nutrients at a year prior to diagnosis. The questionnaire covered 90 foods and used photographs to assist in determining portion size. Subjects were questioned about menstrual and childbearing history, oral contraceptive use, breastfeeding, smoking, family history of breast cancer, and benign breast disease.
In postmenopausal women, no additional benefit from soy was revealed after adjustment for confounding variables. In premenopausal women adjusted for age at birth of first child and nulliparity, there was a statistically significant decrease in risk (P = 0.02) for those women who had high intakes of soy protein. Potential biases include recall bias and the absence of information about mammogram frequency.
In 1996, Wu et al conducted a population-based, case-controlled study of breast cancer risk in Asian women in the United States.7 Controls were matched only on age, ethnicity, and area of residence. Dietary information was gathered during an in-person interview; no follow-up or intervention was undertaken. Food frequency questionnaires were used to assess tofu intake; portion sizes were not assessed.
Asian-American women born in Asia ingested tofu more than twice as often as those born in the United States (62 times per year vs. 30 times per year). For each additional serving of tofu per week, the odds ratio or relative risk estimates for an additional serving of tofu was 0.85 with 95% probability that the relative risk is between 0.74-0.99. In both premenopausal and postmenopausal women, the risk of breast cancer decreased with increased frequency of tofu ingestion even after adjusting for age, study area, ethnicity, and migration history. Bias in this study includes matching; patients’ family histories of breast cancer were not matched.
In 1997, Ingram et al carried out a case-controlled study in Australia to assess the association between phytoestrogen intake and risk of breast cancer by measuring urinary excretion of phytoestrogens over 72 hours.8 Women with newly diagnosed breast cancer were paired with controls matched for age and area of residence. Each woman collected three consecutive 24-hour urine specimens. Phytoestrogen intake was assessed by measuring urinary excretion of daidzein, equol, and the lignans enterodiol, enterolactone, and matairesinol by gas chromatography-mass spectrometry (GC-MS). Genistein, a major phytoestrogen in soy, was not assessed because of technical difficulties with measurement. For the final analysis, 144 pairs of women were available.
After adjustments were made for confounding variables, the risk for the highest quartile of excretion of equol was associated with a fourfold reduction in risk of breast cancer development (trend P = 0.009). Similarly, a threefold reduction in risk (trend P = 0.013) was associated with those individuals with the highest compared with the lowest quartile of enterolactone excretion. Although the other phytoestrogens evaluated did show a trend toward reduction in risk, none reached statistical significance. The data were analyzed separately for premenopausal and postmenopausal women; trends were analogous for each group.
The study weaknesses are the short data-collection period (72 hours) with uncertain correlation to daily phytoestrogen intake.
| Table 2-Isoflavone content in soy products | ||||||
| Soy Product | Mean Genistein Content* | Number of Products Analyzed | Mean Daidzein Content* | Number of Products Analyzed | Mean Total Isoflavone Content* | Number of Products Analyzed |
| Textured soy flour | 78.90 | 8 | 59.62 | 8 | 148.61 | 8 |
| Mature dry-roasted soybean seeds | 65.88 | 8 | 52.04 | 7 | 128.35 | 7 |
| Instant soy powder | 62.18 | 6 | 40.07 | 6 | 109.51 | 6 |
| Soy protein isolate | 59.62 | 14 | 33.59 | 14 | 97.43 | 14 |
| Natto (boiled and fermented soybeans) | 29.04 | 7 | 21.85 | 5 | 58.93 | 5 |
| Mature boiled soybeans (unsalted) | 27.71 | 1 | 26.95 | 1 | 54.66 | 1 |
| Soybean chips | 27.45 | 1 | 26.71 | 1 | 54.16 | 1 |
| Tempeh | 24.85 | 6 | 17.59 | 6 | 43.52 | 6 |
| Miso | 24.56 | 9 | 16.13 | 7 | 42.55 | 7 |
| Soy fiber | 21.68 | 2 | 18.80 | 2 | 44.43 | 2 |
| Soy cheese | 20.08 | 2 | 11.24 | 2 | 31.32 | 2 |
| Soybean cheese curd | 19.20 | 1 | 9.00 | 1 | 28.20 | 1 |
| Firm silken tofu | 15.58 | 2 | 11.13 | 2 | 27.91 | 2 |
| Immature boiled soybeans (unsalted) | 6.94 | 1 | 6.85 | 1 | 13.79 | 1 |
| Soy milk | 6.06 | 16 | 4.45 | 14 | 9.65 | 14 |
| *mg/100 g edible portion | ||||||
| Adapted from:USDA-Iowa State University Database on the Isoflavone Content of Foods-1999. Accessed at: http://www.nal.usda.gov/fnic/foodcomp/Data/isoflav/isfl_tbl.pdf. Accessed: September 17, 1999. | ||||||
Adverse Effects
Soy is used worldwide as a food, especially in Asian cuisine, without any known adverse effects. Allergy is rare. No documented cases were found regarding harmful effects associated with ingesting too much soy.
Food Intake
How much and what type of soy is optimal to reduce the risk of breast cancer remain uncertain. Currently, a wide array of soy products is available including whole soybeans, tofu, tempeh, miso, soy powder, textured soy protein isolate, and soy protein concentrate. (See Tables 1 and 2 for phytoestrogen content in soy foods and soy products.) Recently, purified isoflavonoid pills and powders have reached the market. Though some animal and in vitro models are examining the use of these pills and powders, no human studies exist. These products in particular cannot be recommended with available data since safety and efficacy have yet to be demonstrated. Additionally, soy sauce and soy protein products that are washed with aqueous alcohol during processing lose isoflavones and do not confer isoflavonoid benefits.
Conclusion
As always, it is perplexing to translate epidemiologic studies into a dietary prescription. Although some of the epidemiological studies show a reduction in breast cancer risk, the results are not consistent. However, a significant trend for premenopausal women, which needs to be further elucidated, does appear to exist. In this particular group, the data suggest risk reduction for breast cancer with increased ingestion of soy.
Recommendation
The lack of double-blind, placebo-controlled studies of the association between soy and breast cancer risk make a definite recommendation difficult. Since soy confers other health benefits, i.e., a good source of low-cholesterol, vegetarian protein, health care providers may recommend on that basis that women make soy part of their regular diet.
Dr. Tillem is a Fellow in Integrative Medicine and Health Services Research and Dr. Hardy is Medical Director at Cedars-Sinai Integrative Medicine Medical Group in Los Angeles. Dr. Hardy is Associate Clinical Professor of Medicine at the University of Southern California in Los Angeles.
Food sources of soy include all of the following except:
a. tofu.
b. miso.
c. soy sauce.
d. tempeh.
References
1. Adlercruz H, Mazur W. Phyto-oestrogens and western disease. Annals Med (Finnish Medical Society DUODECIM) 1997;29:95-120.
2. Messina MJ, et al. Soy intake and cancer risk: A review of the in vitro and in vivo data. Nutr Cancer 1994;21:113-131.
3. Mayr U, et al. Validation of two in vitro test systems for estrogenic activities with zearalenone, phytoestrogens and cereal extracts. Toxicology 1992;74:135-149.
4. Clarke R, et al. Estrogens, phytoestrogens, and breast cancer. In: American Institute for Cancer Research, ed. Dietary Phytochemicals in Cancer Prevention and Treatment. New York, NY: Plenum Publishing Corporation; 1996:63-85.
5. Record I, et al. The antioxidant activity of genistein in vitro. J Nutr Biochem 1995; 6:481-485.
6. Lee HP, et al. Dietary effects on breast-cancer risk in Singapore. Lancet 1991;337:1197-1200.
7. Wu AH, et al. Tofu and risk of breast cancer in Asian-Americans. Cancer Epidemiol Biomarkers Prev 1996;5:901-906.
8. Ingram D, et al. Case-control study of phyto-oestrogens and breast cancer. Lancet 1997;350:990-994.
October 1999; Volume 2: 109-113
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