A Fitting Prescription for All:Whole Soyfoods as Part of aVaried Plant-Based Diet

The review in this issue of ONCOLOGY by Messina and colleagues concisely and appropriately summarizes the clinical and epidemiological evidence that consumption of soyfoods is not associated with higher breast cancer recurrence or risk of primary cancer. Consistent with the position of the American Cancer Society and the American Institute for Cancer Research, the authors recommend that clinicians should consider soyfood consumption as part of a healthy varied diet for breast cancer patients and survivors; they describe the lack of clinical evidence for adverse effects of soy on the course of breast cancer, and point to evidence of other health benefits of soyfoods, in particular those related to cardiovascular disease. Additional available data support this recommendation.

Metabolism of Isoflavones in Rodents vs Humans

Since human and mouse studies have shown conflicting results regarding the effect of soy isoflavones on mammary tumors, Setchell et al have studied whether the phase II metabolism of soy isoflavones differs between humans and rodents.[1] Doerge et al have pointed out that phase II metabolism by glucuronidation is a major pathway for the elimination of isoflavones in humans,[2] and others have reported that humans have a high capacity for conjugation of steroid and steroid-like molecules between the intestinal tract and liver, such as endogenous estrogens, thus circulating unconjugated isoflavones remain at a relatively low level.[3] Therefore, Setchell et al provided various soyfoods, or genistein, or pure S-(-) equol to healthy human subjects (adults and infants), Sprague-Dawley rats, and multiple mouse strains: athymic nude, C57BL/6, and transgenic AngptL4B6 mice (an angiogenesis model). They then analyzed the plasma concentrations of unconjugated (biologically active) vs conjugated forms of genistein by liquid chromatography–tandem mass spectrometry (LC-MS/MS). Strikingly, the unconjugated genistein levels in plasma were found to be 20 to 150 times higher in the rodents than in all the human subjects.[1] These data further support the contention that rodents may not be appropriate models for gaining insight into the health effects of isoflavones in humans, because it is very unlikely that the high unconjugated plasma concentrations of genistein seen in rodents would occur in humans who consume soyfoods or isoflavone supplements, due to the very high capacity for phase II metabolism of isoflavones.

Breast Concentration of Isoflavones

Two recent studies with pre- and postmenopausal female cynomolgus monkeys suggest that dietary exposure alone of soy protein for periods of 12 to 36 months, as the human equivalent of 129 mg/d of isoflavones (containing 91-mg genistein, 31-mg daidzein, and 7-mg aglycone equivalents of glycitein) is not a significant estrogen agonist for breast tissue.[4,5] This dietary exposure did not induce proliferation in mammary tissue; instead, mammary gland proliferation (Ki67 labeling index) induced by estradiol was antagonized by soy in postmenopausal monkeys. In humans, studies of breast tissue isoflavones concentrations following exposure to dietary soy products are also reassuring. In two small trials, women undergoing aesthetic breast reductions tested a several-day intervention of soy supplementation and/or soy milk, followed by measurement of isoflavones (genistein, daidzein, and equol) by LC-MS/MS in breast tissue compared with serum and urinary levels.[6,7] Both studies found that concentrations of total isoflavones were in the subnanomolar[7] to low nanomolar[6] ranges in hydrolyzed breast tissue, whereas they were generally 100-fold higher in the corresponding serum and urine samples; thus serum concentrations may overestimate tissue exposure.

Ethnic Differences in Metabolism of Isoflavones

The majority of intervention studies have consisted of women of European ancestry, and differences in biomarkers between Asians and Europeans have not often been compared. Asian women tend to have higher mammographic density (due to the smaller breast sizes) than Caucasians,[8] and are less likely to produce nipple aspirate fluid (NAF)[9,10] but more likely to produce equol.[11] Existing data suggest that soy ingestion may have a greater association with mammographic density[12] and possibly estrogen levels in Asians[13] than in Europeans. However, low NAF production and a lack of breast tissue measurement in Asian women have made it difficult for researchers to investigate the effect of soy on local breast biomarkers. Two possible mechanisms vary across populations and appear to be important in terms of beneficial effects of soy for breast cancer patients: (1) genetic variation in the metabolism of enzymes such as cytochrome P450 or catechol-O-methyltransferase[14,15]; and (2) the timing of soy exposure, occurring in early childhood in Asian women rather than as part of adult nutrition, which is more common among Western women. Gut microbiota colonize the intestine during infancy[16] and facilitate the hydrolysis of glycosides for improved bioavailability and the formation of equol from daidzein.[17]

Signs of Breast Proliferative Response to High-Dose Soy Supplements

Finally, the issue of proliferative response in the breast epithelium of premenopausal women given a soy isoflavone supplement needs to be addressed[18,19]; cell proliferation in normal breast tissue is a surrogate marker for adverse effects on the breast, and agents that increase it are generally considered to increase cancer risk. The evidence suggesting a pro-estrogenic effect of soy components on the breast comes not only from research linking soy with increased cell proliferation in premenopausal women,[18] but also from a gene expression signal consistent with induction of estrogenic pathways, described in the same study. Additionally, in a study examining nipple fluid biomarkers following soy supplementation, levels of pS2 in nipple fluid were increased, although cell proliferation was not.[19] Other studies examining this issue have been small, the interventions have been short-term,[20] and the fraction of patients yielding samples sufficient for Ki67 evaluation has been low.[21] Thus although there is no robust evidence of harm in the form of increased cancer rates or mortality, studies that show no effect on proliferation are limited and do not fully counter the possibility of a weak pro-estrogenic effect of soy on the breast. The injunction against processed forms of soy does not pose any hardship to women who want to consume soyfoods as part of a healthy, varied, plant-based diet. It does not deprive women of the healthful effects of soy consumption on other organs. Therefore, until better evidence is available for the effects of soy on women from non–soy-consuming countries, it seems reasonable to limit consumption to soyfoods, and to avoid high-dose supplements of processed soy components.

Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

References

1. Setchell KD, Brown NM, Zhao X, et al. Soy isoflavone phase II metabolism differs between rodents and humans: implications for the effect on breast cancer risk. Am J Clin Nutr. 2011;94:1284-94.

2. Doerge DR, Chang HC, Churchwell MI, Holder CL. Analysis of soy isoflavone conjugation in vitro and in human blood using liquid chromatography-mass spectrometry. Drug Metab Dispos. 2000;28:298-307.

3. Gu L, House SE, Prior RL, et al. Metabolic phenotype of isoflavones differ among female rats, pigs, monkeys, and women. J Nutr. 2006;136:1215-21.

4. Wood CE, Register TC, Cline JM. Soy isoflavonoid effects on endogenous estrogen metabolism in postmenopausal female monkeys. Carcinogenesis. 2007;28:801-8.

5. Wood CE, Kaplan JR, Stute P, Cline JM. Effects of soy on the mammary glands of premenopausal female monkeys. Fertil Steril. 2006;85(suppl 1):1179-86.

6. Maubach J, Depypere HT, Goeman J, et al. Distribution of soy-derived phytoestrogens in human breast tissue and biological fluids. Obstet Gynecol. 2004;103:892-8.

7. Bolca S, Urpi-Sarda M, Blondeel P, et al. Disposition of soy isoflavones in normal human breast tissue. Am J Clin Nutr. 2010;91:976-84.

8. Maskarinec G, Pagano I, Chen Z, et al. Ethnic and geographic differences in mammographic density and their association with breast cancer incidence. Breast Cancer Res Treat. 2007;104:47-56.

9. Maskarinec G, Morimoto Y, Conroy SM, et al. The volume of nipple aspirate fluid is not affected by 6 months of treatment with soy foods in premenopausal women. J Nutr. 2011;141:626-30.

10. Petrakis NL, Lee MM, Wrensch MR, et al. Birthplace and yield of nipple aspirate fluid in Chinese women. Cancer Epidemiol Biomarkers Prev. 1998;7:835-9.

11. Lampe JW. Is equol the key to the efficacy of soy foods? Am J Clin Nutr. 2009;89:1664S-1667S.

12. Ursin G, Sun CL, Koh WP, et al. Associations between soy, diet, reproductive factors, and mammographic density in Singapore Chinese women. Nutr Cancer. 2006;56:128-35.

13. Hooper L, Ryder JJ, Kurzer MS, et al. Effects of soy protein and isoflavones on circulating hormone concentrations in pre- and post-menopausal women: a systematic review and meta-analysis. Hum Reprod Update. 2009;15:423-40.

14. Thompson PA, Ambrosone C. Molecular epidemiology of genetic polymorphisms in estrogen metabolizing enzymes in human breast cancer. J Natl Cancer Inst Monogr. 2000;125-34.

15. Zhu BT. Catechol-O-Methyltransferase (COMT)-mediated methylation metabolism of endogenous bioactive catechols and modulation by endobiotics and xenobiotics: importance in pathophysiology and pathogenesis. Curr Drug Metab. 2002;3:321-49.

16. De FC, Cavalieri D, Di PM, et al. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc Natl Acad Sci USA. 2010;107:14691-6.

17. Lampe JW. Emerging research on equol and cancer. J Nutr. 2010;140: 1369S-1372S.

18. Khan SA, Chatterton RT, Michel N, et al. Soy isoflavone supplementation for breast cancer risk reduction: a randomized phase II trial. Cancer Prev Res (Phila). 2012;5:309-19.

19. Hargreaves DF, Potten CS, Harding C, et al. Two-week dietary soy supplementation has an estrogenic effect on normal premenopausal breast. J Clin Endocrinol Metab. 1999;84:4017-24.

20. Sartippour MR, Rao JY, Apple S, et al. A pilot clinical study of short-term isoflavone supplements in breast cancer patients. Nutr Cancer. 2004;49:59-65.

21. Cheng G, Wilczek B, Warner M, et al. Isoflavone treatment for acute menopausal symptoms. Menopause. 2007;14:468-73.