Singling Out Soy: Scientists probe potential anticancer benefits of a long-time Asian diet staple

MORE STUDY NEEDED: Mark Messina, a nutrition consultant, says Lamartiniere's findings are an "exciting hypothesis," but he notes that epidemiological studies linking soy and breast cancer rates have mixed results. Soy is a hot topic these days, not only among farmers--who have planted a record 71.7 million acres of soybeans, according to the U. S. Department of Agriculture--but among scientists who are exploring and debating the health benefits of a food that for thousands of years has been a staple in Asian diets. Driving the interest in soy is the finding that Asian women have extremely low breast cancer rates and eat diets rich in soy. Moreover, as the diets of Asian immigrants to the West change in favor of more fat and meat, breast cancer rates increase. Consequently many researchers have singled out soy as a potential breast cancer preventive. According to the American Cancer Society, there will be 178,700 new cases of breast cancer this year in the United States, and breast cancer will kill an estimated 43,500 women this year, second to lung cancer. The United Soybean Board, an organization funded by soybean farmers, spent $3.25 million on "health-related research" on soybeans, according to Debra Carnes, board spokesperson. And the National Cancer Institute's Diet and Cancer Branch has committed $4.9 million to five projects of outside researchers who are trying to determine how soy consumption might prevent breast cancer. NCI also is funding a clinical trial, under the guidance of Ann Kennedy, Richard Chamberlain professor of research oncology at the University of Pennsylvania, and Frank Myskens, director of the Clinical Cancer Center at the University of California, Irvine, to determine if a soy constituent called Bowman-Birk Inhibitor, a protease inhibitor, can treat oral leukoplakia, a potential precursor of oral cancer. But much of the work on soy today focuses on phytoestrogens, or estrogen compounds found in plants. The soy phytoestrogen generating the most interest it seems is genistein (5,7,4'-trihydroxyisoflavone). In fact, NCI Diet and Cancer Branch research is focused entirely on genistein. And apparently recognizing interest in soy as a potential anticancer weapon, food processing giant Archer Daniels Midland notified the Food and Drug Administration in February that in a review of scientific literature it has determined soy isoflavones are generally recognized as safe, and the company "anticipates that soy isoflavones will not only be added to the diet by direct addition to conventional foods, but also as dietary supplements." An ADM spokesperson declined to discuss details, saying he wanted the legal process to run its course. "It [genistein] is quite capable of being preventive, at least in our animal work," says Stephen Barnes, professor of pharmacology and toxicology at the University of Alabama at Birmingham, who has studied the effect in rats, with NCI support. DOSE RESPONSE EFFECT: Coral Lamartiniere of the University of Alabama at Birmingham reports that animals getting higher levels of genistein in the diet had fewer signs of tumors. Coral Lamartiniere, professor of pharmacology and toxicology and senior scientist at the Comprehensive Cancer Center at the University of Alabama at Birmingham has found that rats exposed to dietary genistein from conception to 21 days after birth had fewer breast tumors from exposure to DMBA (dimethylbenz[a]anthracene), a known carcinogen, than control animals (W.A. Fritz et al., Carcinogenesis, in press). Moreover, Lamartiniere reports a dose-response effect: animals getting higher levels of genistein in the diet had fewer signs of tumors. The animals were treated with DMBA at 50 days after birth, about a month after their genistein-laced diets were replaced with ordinary rat food. The basis of the protection, according to Lamartiniere, lies in the differentiation of breast cells apparently induced by genistein. Cells that are differentiated undergo a range of changes in structure and expression of enzymes. Increased differentiation changes the structure of cells into lobules, which are less susceptible to carcinogens. "What we've concluded is that the early period of life is the most susceptible for causing differentiation to occur. Once it occurs, you're protected. If you give it [genistein] later in life, there is some evidence that will show you will get protection, but you will get less protection," says Lamartiniere. But Claude Hughes, director of the Center for Women's Health at Cedars-Sinai Medical Center in Los Angeles, questions the relevance of the DMBA model, arguing that the oncogene involved in DMBA-induced cancer is ras, and "that oncogene is virtually never involved in the breast cancers that occur in humans, " he says. NOT PERSUADED: Daniel Sheehan of the National Center for Toxicological Research says better definition is needed of the benefits and risks of genistein. Lamartiniere dismisses that criticism, arguing that DMBA-induced breast cancer involves more than the ras oncogene. "Breast cancer induced by DMBA is very similar to human carcinogenesis in that it is hormone-dependent," he says. Genistein, he finds (N.M. Brown et. al., Molecular and Cellular Endocrinology, in press) alters the epidermal growth factor (EGF) receptor, making cells less responsive to the promotional effects of estrogen. In research with human subjects, Lee-Jane Lu, associate professor of preventive medicine and community health at the University of Texas Medical Branch in Galveston, finds in a study of a few women that diets containing genistein lengthened the menstrual cycle by an average of three days. The women had lower levels of estrogen and progesterone in their blood while on the genistein-containing diet (L-J. Lu et al., Cancer Epidemiology, Biomarkers & Prevention, 5:63-70, 1996). "In breast cancer etiology the dominant hypothesis is that cumulative exposure to combined progesterone and estrogen in the menstrual cycle is bad and tends to promote the highest proliferation of breast cancer cells," says Peter Gann, associate professor of preventive medicine at Northwestern University Medical School. Consequently lengthening the menstrual cycle, says Gann, could lower cumulative exposure to those hormones. "In high-risk populations cycles tend to be shorter than they are in lower risk populations," he says, pointing to Japanese women and vegetarians who are likely to have longer menstrual cycles. What is happening, in the view of Kenneth Setchell, professor of pediatrics at Children's Hospital Medical Center of the University of Cincinnati, is that the follicular phase of the cycle, during which estrogen levels are low, is lengthened, so over a lifetime a woman experiences lower estrogen levels. Consequently estrogen's ability to promote cancers is reduced, he says. Society for Experimental Biology and Medicine 162 W. 56th St., Suite 203 New York, NY 10019 Telephone: (212) 541-7855; * Fax (212) 541-7503 Executive Director: Felice O'Grady 1500 members www.sebm.org United Soybean Board c/o 190 Queen Anne Ave. N. Seattle, WA 98109 Telephone: (800) 825-5769; * Fax (206) 270-4656 www.talksoy.com E-mail: inform@talksoy.com National Cancer Institute Diet and Cancer Branch, EPN 212 9000 Rockville Pike Bethesda, MD 20892 Telephone: (301) 496-8573; * Fax: (301) 402-0553 or 301 594-2943 www.nci.nih.gov (under constructino) Gann and Linda Van Horn, professor of preventive medicine at Northwestern University Medical School, are conducting a three-month study of approximately 200 women, half of whom are getting soy isoflavones, including genistein, in combination with a low-fat, high-fiber diet. The diet of a control group will be the same except for the absence of the soy addition. The goal, says Gann, is to determine if the soy diet can, in fact, lengthen the menstrual cycle on a long-term basis. The three-month period will be preceded by a year's study in which women will be randomly assigned to either a group receiving a high-fiber, low-fat diet or one that will eat a usual diet. But if in fact this does translate to breast cancer protection, the mechanism is not certain. While Lamartiniere points to genistein's role in cell differentiation, Gann notes there are other hypotheses. As one example, he says that genistein has been hypothesized to cause the liver to increase sex hormone binding globulin (SHBG), which "ties up estrogen." While much of the interest in soy's potential to prevent breast cancer is based on the low rates of the disease among Asian women, Mark Messina, an independent nutritional consultant in Port Townsend, Wash., says such evidence is "equivocal." While labeling Lamartiniere's animal findings an "exciting hypothesis," he also notes that epidemiological studies of the link between soy consumption and breast cancer in Asia have mixed results. One study (H.P. Lee et al., Lancet, 337:1197-1200, 1991) that garnered a lot of publicity found soy intake was associated with lower incidence of premenopausal but not postmenopausal breast cancer. Post menopausal breast cancer is by far more common in the United States than premenapausal. Two other epidemiological studies since then (K. Hirose, Japanese Journal of Cancer Research, 86:146-54, 1995; J-M. Yuan, British Journal of Cancer, 71:1353-8, 1995) also failed to find a soy consumption associated with lower postmenopausal breast cancer rates. Combined with questions about soy's efficacy, there are also concerns about its potential for harm. Daniel Sheehan, director of the Estrogen Knowledge Base Program at the National Center for Toxicological Research of the FDA, argues more data are needed about genistein. (D. Sheehan, Proceedings of the Society for Experimental Biology and Medicine, 217:379-84, March 1998). "As we explore these kinds of chemicals, we have to define the benefits and the risks and the circumstances under which they occur and be prepared to make a determination whether the chemical is safe enough with certain kinds of precautions for exposure to occur," says Sheehan, who notes he is not speaking for the FDA. But Setchell says soy has been eaten for thousands of years in Asia, with no apparent harm coming to those who ingest it. The same holds for infants being fed soy infant formula, which has been used in the West for decades. "The pediatric literature is not flooded with reports of adverse effects. One would have expected some sort of reports to have surfaced in the literature had this been a major problem," maintains Setchell. whose work has been partially funded by makers of soy formulas. He says, however, that funding did not occur until after his initial work claiming benefits of soy was published. Such research, he says, has been supported by U.S. government agencies. Image courtesy Fairview Farms Sheehan, however, is not persuaded by such arguments, saying fetal alcohol syndrome, which occurred for many years and apparently was ignored for many years before being recognized as a disorder. Setchell and others doing research on soy note that taking large amounts of soy through supplements may lead to harm, but consuming soy as part of a diet is unlikely to lead to ingesting the large amounts that may cause harm. Meanwhile, in a one-month trial of Bowman-Birk Inhibitor Concentrate (BBIC) involving 11 patients with 31 lesions, 65 percent of the lesions regressed or resolved, according to an unpublished executive summary. Two new lesions did appear, however. The researchers report that "no adverse effects" occurred. The summary on the trials adds the disclaimer that "these data are very preliminary and no conclusions regarding the efficacy or toxicity of BBIC should be made." In an interview, however, Kennedy says she is enthusiastic about its potential. However, she admits she is uncertain how BBI prevents cancer. BBI, she says, is well known for its ability to inhibit proteases. "The question is how those fit into the mechanistic scenario involved in cancer development," she says. Whether soy will in fact live up to its reputation for enhancing health is yet to be determined. In the interim it is apparent that the research being done on the impact of soy and its constituents is likely to provide researchers with much more knowledge on basic biological processes. Harvey Black, a freelance science writer in Madison, Wis., can be reached online at 73773.2227@compuserve.com.

Singling Out Soy: Scientists probe potential anticancer benefits of a long-time Asian diet staple

Interested in reading more?

Become a Member of