By Lynn Keegan, RN, PhD, HNC, FAAN, and Gerald T. Keegan, MD, FACS
Soybean protein and other phytoestrogens have been popularized in the lay press both as being preventives for breast cancer as well as for treatment of menopausal symptoms. The scientific evidence for these effects is not clear and, at times, is confusing. Because of the lower incidence of both hot flashes and breast cancer in Asian women than women of other racial origins, a hypothesis has emerged in the scientific community suggesting that the lower incidence of both these phenomena might be related to the increased consumption of isoflavone-containing soy products in the Asian diet.1 The results of scientific investigations have been contradictory. Although most animal studies have shown a relationship between soy protein consumption and breast cancer preventive effects, a few studies have suggested that soy phytoestrogens may stimulate breast cancer cell growth under certain circumstances.2 Whether phytoestrogens have any effect at all in humans is debated and the data are still unclear.
A related dilemma recently has developed for women who take estrogen/progestin compounds for the prevention of menopausal symptoms. Results from the Women’s Health Initiative3 and the long-term follow-up of the Heart and Estrogen/Progestin Replacement Study4 show an increased risk of both cardiovascular disease and breast cancer among women randomized to hormone therapy.5 For this reason, many women are seeking alternatives to prescribed estrogen/progestin compounds and have started using dietary supplements containing isoflavones derived from soy protein and red clover.6,7 A recent study suggests that although isoflavones can have some biological activity, the substances tested in this study had no clinically important effect on hot flashes or other menopausal symptoms.8
Constituents and Metabolism
An annual legume of the Fabaceae or Legumenosae family (Glycine max.), soybeans originated in Asia, have been cultivated widely for more than 2,000 years, and have been widely consumed by more than a fourth of the world’s population.9 Products derived from soybeans include tofu, miso, and soy milk. These products contain several different classes of phytoestrogens. The three main classes are the isoflavones, coumestans, and lignans.10 Some of these agents are thought to have antioxidant, antibacterial, anti-angiogenic, antiproliferative, and antiparasitic effects, but only four (genistein, daidzein, biochanin, and formononetin) have potent phytoestrogenic activity.10 Little data are available on the quantitative absorption, protein-binding, or the specific metabolism of dietary estrogens. It is known that dietary phytoestrogens are metabolized by intestinal bacteria, absorbed and then conjugated in the liver, circulated in the plasma, and excreted in the urine.11
There are no data on the developmental effects in humans of soy protein. This leads one to question whether the age of the individual at the initiation of a phytoestrogen-rich diet will affect the eventual effect of phytoestrogens on breast cancer prevention, and whether intake at an early age specifically will condition the receptors.11 One study supporting results of immigration and epidemiological studies concluded that soy protein might be beneficial in the prevention of breast cancer, but only if consumed in early life or in adolescence.10,12 This is confirmed by a study that measured soy protein intake and breast cancer risk in Asian women of mixed origin during adolescence and adulthood. Subjects who were high consumers during adolescence and adulthood showed the lowest risk. The risk was intermediate in those who were high consumers during adolescence and low soy consumers during adult life. The risk did not appear to be different between those who were low consumers during adolescence and high consumers during adulthood, leading to the conclusion that high soy intake during childhood among Asian-Americans is associated with reduced breast cancer risk.13
Proposed Mechanisms of Action as a Modifier of Breast Cancer
Isoflavones are polyphenolic compounds that are structurally related to estrogens. These so-called phyto- estrogens bind to estrogen receptors14 and have greater affinity for estrogen receptor beta than alpha.15 These agents also may act as partial agonists in some tissue and antagonists in others, which leads to the conclusion that these compounds may exert tissue-specific effects. The postulation that these agents might be effective for breast cancer prevention at least partially is contingent upon the presence, quantity, and type of estrogen receptor in tissue with the potentiality of developing into cancer in high-risk individuals. If this is their sole mechanism of action, phytoestrogen compounds would not be expected to have any impact on the 30% of breast cancers that are estrogen receptor-negative.16
The effect of soy protein may be more complex and is mediated only partially by the alteration of estrogen receptors.17 Photochemicals also may act synergistically as demonstrated in the induction of cellular growth arrest in response to DNA damage (GADD) produced by a combination of dietary-available indole-3-carbinol (I3C) with genistein.18 This demonstration of synergism suggests the possibility that the preventive dietary effects noted in specific Asian populations may not be related to a single agent, but rather may result from different dietary components acting together. The effects of soybean genistein were compared with a commercially available isoflavone soy extract containing several different soy proteins to determine the effect on the growth of F3II mouse mammary adenocarcinoma cells.19 The study concluded that the inhibition of cell growth, although noted in both groups, was of greater magnitude in the genistein-containing soy extract cohort than in the group receiving an equivalent amount of genistein alone. The study also concluded that this was due in part to the specific effects on the specific cell cycle regulatory proteins.
Another example of interaction is seen between phytoestrogens and vitamin D. A steroid hormone derived from vitamin D(3)—1,25-dihydroxyvitamin D(3) (1,25(OH)(2)d(3))—is known to be a negative growth regulator of breast cancer cells. Reservadol, a soy-derived phytoestrogen, has been shown to sensitize breast cancer cells to the growth inhibitory effects of vitamin D.20
Another postulated mechanism of action involves the generation of reactive oxygen species (ROS). The effect of fermented soy protein was tested on several different human breast cancer cell lines and was found to have an inhibitory effect. The inhibitory effect seemed to be caused by the additive effect of a wide variety of constituents and actual cell apoptosis occurred. Growth inhibition and ROS generation induced by the fermented soy protein was inhibited by catalase and deferoximine, indicating that ROS was the cause of cell apoptosis.21 Studies in cell culture also have demonstrated that genistein-induced inhibition of cell division is mediated partly by decreased telomere length, reduced mitosis, and inhibition of Akt activation, leading to induction of apoptosis.22
Breast cancer prevention trials studied several different allopathic agents. The two most common agents are tamoxifen and raloxifene. Tamoxifen has been demonstrated in five different studies to reduce the risk of estrogen receptor-positive breast cancer.23 Tamoxifen is a non-steroidal anti-estrogen. The anti-estrogen may be related to its ability to compete with estrogen for binding sites in target tissue. In animal models, tamoxifen appears to exert its antitumor effects by binding estrogen receptor sites, and in in vivo experiments tamoxifen has been found to compete with estradiol for estrogen- receptor protein.24 However, a significant incidence of uterine malignancies, both adenocarcinoma and uterine sarcoma as well as stroke and pulmonary embolism, has been found in high-risk women using tamoxifen in breast cancer prevention trials.24 For this reason, the use of this drug has not been advocated extensively except in very high-risk individuals.
There is perhaps more hope for the use of raloxifene. The actions of raloxifene also are mediated by estrogen receptors, but in some cases raloxifene will activate certain estrogenic pathways and in others it will produce a blockade, acting as an agonist in some receptors and as an antagonist in others. The technical term for this class of agents is a selective estrogen receptor modulator (SERM). Raloxifene apparently blocks and does not stimulate the estrogen receptors in breast and uterine tissue, yet it will decrease the absorption of bone and reduce biochemical markers of bone turnover in postmenopausal women to premenopausal levels.25 For this reason raloxifene has been considered safe for the prevention of osteoporosis in women at high risk for breast cancer and more recently its effectiveness in the prevention of breast cancer has been studied. The results of those studies have not as yet been compiled. Raloxifene also carries the risk of significant side effects including thromboembolic complications.16 Both tamoxifen and raloxifene are very expensive.
Another class of agents being tried in breast cancer prevention is the aromatase inhibitors (AI). These agents have fewer side effects than tamoxifen or raloxifene, inhibit estrogen synthetase, and potentially offer the benefit of reducing the catechol estrogen metabolites, which play a role in the initiation of breast carcinogenesis.26
Ideally, a chemopreventative agent used in an otherwise healthy population should be effective, nontoxic, safe for long-time use, convenient, inexpensive, and have minimal side effects. The fact that soy proteins may act as either agonists or antagonists at the level of the estrogen receptor and may act as SERMs leads us to speculate that these proteins will act in preventing breast cancer in the same way as is postulated for raloxifene, yet not carry the side effects or the expense.
A study in China demonstrated that cell apoptosis in breast cancer cell lines (MCF-7 and T47D) was induced by genistein in a manner similar to that of tamoxifen.27 It is possible that a naturally occurring, inexpensive, dietary substance with minimal side effects might work as well as the more expensive and toxic agents in the prevention of breast cancer. However, the results of studies in human subjects have been inconsistent and somewhat discouraging. For example, one Chinese study comparing the dietary choices of 200 women with breast cancer with adequately matched controls suggested that soy product intake had a protective effect in premenopausal women but no effect in the postmenopausal group.28 Another similar study in China found no statistically protective effect of soy protein in either pre- or post-menopausal women.29 However, a relationship clearly was established in a study showing that both pre- and post-menopausal women with breast cancer excreted much lower amounts of phytoestrogens,30 but a study of Dutch menopausal women showed no significant breast cancer risk reduction in women with a high phytoestrogen excretion.10 A study of more than 800 Japanese women demonstrated that frequent consumption of miso soup and other isoflavones was associated with a lower risk of breast cancer.31 A recent review of 18 human studies of a dietary relationship of breast cancer risk to soy protein intake showed no protective effect of the consumption of phytoestrogens with the possible exception of women who consumed phytoestrogens at adolescence or at very high doses.10 Only four of these studies were prospective and none of them demonstrated a risk reduction.
Adverse Effects of Soy Protein
The consumption of soy protein generally is considered to be beneficial and possibly have protective effects against several common maladies. However, because of the estrogenic activity of these substances, negative effects have been postulated, but there is scant evidence to support this contention.32 A study to evaluate the pharmakinetics and safety of a purified unconjugated isoflavone preparation that delivered single genistein doses of 2, 4, 8, or 16 mg/kg body weight showed minimal toxicity in healthy postmenopausal women, and the pharmacokinetic data suggested that chronic 12-24 hour dosing would not lead to progressive accumulation.33 An investigational soy isoflavone drug product (PTI G2535) was tested for toxicity and teratogenic effects. Although no toxicity was noted, there remained the concern that isoflavones, specifically genistein, could inhibit topoisomerase and possibly lead to DNA strand breaks. Although there was a statistically significant increase in the frequency of micronucleated polychromatic erythrocytes in the male rats, the increases were small, not dose-related, and spontaneously resolved. In this study, dietary genistein had no negative effects on survival, weight gain, or the incidence or types of tumors that developed in cancer-prone rodents lacking the p53 suppressor gene.34
The data at this point, although quite intriguing, do not suggest that any soy protein-specific dietary supplements or dietary changes are helpful in preventing the emergence of breast cancer in adults. The data do suggest that long-term use of soy protein beginning in childhood and continuing through the developmental years into adolescence may be protective against the emergence of breast cancer. There appears, however, to be little harm and perhaps some benefit in pursuing a soy protein-rich diet.
Dr. Gerald Keegan is Emeritus Staff, Scott & White Clinic and Hospital, Temple, TX, and former Professor of Surgery, Texas A&M University School of Medicine. Lynn Keegan, Director, Holistic Nursing Consultants, Port Angeles, WA, is on the Editorial Board of Alternative Therapies in Women’s Health.
1. Boulet MJ,et al. Climacteric and menopause in seven Southeast Asian countries. Maturitas 1994;19:177-182.
2. Kurzer MS. Phytoestrogen supplement use by women. J Nutr 2003;133:1983S-1986S.
3. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progesterone in healthy postmenopausal women: Principal results from the Women’s Health Initiative randomized control trial. JAMA 2002;228:321-333.
4. Grady D, et al, for the HERS Research Group. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERSII). JAMA 2002;288:49-57.
5. Hulley S, et al, for the HERS Research Group. Noncardiovascular outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study followup (HERSII). JAMA 2002;288:58-66.
6. The mainstreaming of alternative medicine. Consumer Reports 2000;65:17.
7. Kam IW, et al. Dietary supplement use among menopausal women attending a San Francisco health conference. Menopause 2002;9:72-78.
8. Tice JA, et al. Phytoestrogen supplements for the treatment of hot flashes: The Isoflavin Clover Extract (ICE) Study. JAMA 2003;290:207-214.
9. Harper JE. Soybean. World Book Online Reference Centre. Available at: www.aolsvc.worldbook.aol.com/ar?/na/ar/co/ar522440.htm. Accessed Aug. 7, 2003
10. Peeters PH et al. Phytoestrogens and breast cancer risk. Review of the epidemiological evidence. Breast Cancer Res Treat 2003;77:171-83.
11. Cassidy A. Potential risks and benefits of phytoestrogen-rich diets. Int J Vitam Nutr Res 2003;73:120-126.
12. Adlercreutz H. Phytoestrogens and breast cancer. J Steroid Biochem Mol Biol 2002;83:113-118.
13. Wu AH, et al. Adolescent and adult soy intake and risk of breast cancer in Asian-Americans. Carcinogenesis 2002;23:1491-1496.
14. Martin PM, et al. Phytoestrogen interaction with estrogen receptors in human breast cancer cells. Endocrinology 1978;103:1860-1867.
15. Kuiper GG, et al. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology 1997;138: 863-870.
16. August DA, Toppmeyer DL. Chemoprevention of breast cancer. Am J Oncol Rev 2003;2:325-327.
17. Chen WF, et al. Inhibitory actions of genistein in human breast cancer (MCF-7) cells. Biochem Biophys Acta 2003;1638:187-196.
18. Auborn KJ, et al. Indole-3-carbinol is a negative regulator of estrogen. J Nutr 2003;133(7 Suppl):2470S-2475S.
19. Hewitt AL, Singletary KW. Soy extract inhibits mammary adenocarcinoma growth in a syngeneic mouse model. Cancer Lett 2003;192:133-143.
20. Wietzke JA, Welsh J. Phytoestrogen regulation of a vitamin D3 receptor promoter and 1,25-dihydroxyvitamin D3 actions in human breast cancer cells. J Steroid Biochem Mol Biol 2003;84:149-157.
21. Chang WH, et al. Growth inhibition and induction of apoptosis in MCF-7 breast cancer cells by fermented soy milk. Nutr Cancer 2002;43:214-226.
22. Chinni SR, et al. Pleotropic effects of genistein on MCF-7 breast cancer cells. Int J Mol Med 2003;12: 29-34.
23. Cuzick J. Chemoprevention of breast cancer. Am J Oncol Rev 2003;2:319-321.
24. Physicians’ Desk Reference. 57th ed. Montvale, NJ: Medical Economics Co.; 2003: 675.
25. Physicians’ Desk Reference. 57th ed. Montvale, NJ: Medical Economics Co.; 2003: 1833
26. Goss PE, Strasser K. Aromatase inhibitors in the treatment and prevention of breast cancer. Clin Oncol 2001;19:881-894
27. Yu Z, et al. Genistein induced apoptosis in MCF-7 and T47D cells. Wei Sheng Yan Jiu 2003;32:125-127.
28. Lee HP, et al. Dietary effects on breast-cancer risk in Singapore. Lancet 1991;337:1197-1200.
29. Yuan JM, et al. Diet and breast cancer in Shanghai and Tianjin, China. Br J Cancer 1995;71:1353-1358.
30. Ingram D, et al. Case-controlled study of phyto-oestrogens and breast cancer. Lancet 1997;350:990-994.
31. Yamamoto S, et al. Japan Public Health Center-Based Prospective Study on Cancer Cardiovascular Diseases Group. Soy, isoflavones, and breast cancer risk in Japan. J Natl Cancer Inst 2003;95:906-913.
32. Munro IC, et al. Soy isoflavones: A safety review. Nutr Rev 2003;61:1-33.
33. Bloedon LT, et al. Safety and pharmacokinetics of purified soy isoflavones: Single-dose administration to postmenopausal women. Am J Clin Nutr 2002;76: 1126-1137.
34. Misra RR, et al. Genotoxicity and carcinogenicity studies of soy isoflavones. Int J Toxicol 2002;21:277-285.