October 17th, 2006 by Tori Hudson, N.D.
by Tori Hudson, N.D.
Breast cancer is one of the most important health problems facing Western women today. Approximately 180,000 new cases will be diagnosed in the United States this year and 45,000 women will die from the disease each year. Risk factors for breast cancer incidence are complex, multi-factorial, and not completely understood. Established risk factors include nulliparity, late age at first pregnancy, early menarche, late menopause, obesity, alcoholism, first degree relative with breast cancer, inheritance of BRCA 1 and BRCA 2 gene mutations and exposure to ionizing radiation.
There is also strong epidemiological evidence that diet also has a role in the etiology of breast cancer. This evidence has predominantly come from population studies, and subsequently cohort and case-control studies. Many of these studies have focused on dietary fat and the hypothesis that a diet high in fat can increase the risk of breast cancer. A review of some of the pertinent findings will be helpful in sorting out the complicated data. About 30 years ago, the fat intake of many countries was plotted on a graph against breast cancer rates. With few exceptions, the more dietary fat that individuals in that society consumed, the higher the risk of breast cancer. Ten out of ten international studies looking at large differences in fat intake from one country to another continued to confirm this relationship between higher dietary fat levels and higher rates of breast cancer. By and large, women who live in cultures with the lowest fat intake like Japan and Thailand have the lowest rates of breast cancer. Women in the middle east who have medium amounts of fat in the diet have medium rates of breast cancer. Women in Europe and North America with the highest intake of dietary fat have the highest rates of breast cancer. However, in 1992, the Nurses’ Health Study group found no such link. There have been many critique of this study that have pointed out the inaccuracy of the measurements used and results obtained; but perhaps the most compelling at the time was the criticism of the five categories of dietary fat analyzed. The most glaring deficiency was that the group with the lowest amount of fat was still only slightly lower than 29 percent. This is notably higher than the 20 percent many researchers believe to be the beginning of where women would receive the protective benefit of a low fat diet. In March of 1999, a follow up analysis of 88,795 women extended the Nurses’ Health Study for another 6 years and more than 1500 cases. This extended study is now considered large enough and long enough to assess the effect of less than 20% fat intake as well as examining risks of different types of fat. Surprising to many, they saw no increased risk of breast cancer with increased intake of animal fat, polyunsaturated fat, saturated fat, or trans-unsaturated fat . They also found no evidence of decreased risk of breast cancer with increased intake of vegetable fat or monounsaturated fats. Also contrary to the predominant hypothesis, they observed an increased risk of breast cancer associated with omega-3 fat from fish. The strength of this second report is that the analysis was prospective and included more cases with longer follow-up than the previously studied report. However, the capacity to examine breast cancer risk at the extremes of fat intake is limited by the small proportion of women in those groups and a greater probability of misclassification of dietary intake in these categories.
Numerous other studies have pointed out the protective benefits of olive oil and fish fat. A study published in the Journal of the National Cancer Institute in 1995 demonstrated that increased olive oil consumption was associated by a lowered risk of breast cancer in Greek women by 25%. Two case-control studies, one in Spain and the other in Italy, as well as the Greek study are reasonably large, properly analyzed studies of monounsaturated fat and breast cancer. The Spanish study and the Greek study have similar results, suggesting a protective effect of olive oil. The Italian study found a strong positive association between saturated fat intake and breast cancer risk, but no association with monounsaturated fat intake. Another study in France showed a protective effect between breast cancer and the consumption of olive oil, although it was not considered statistically significant. A recent survey was completed in Sweden studying 61,471 women from 1987 to 1990. They reported that monounsaturated fat reduced the risk of breast cancer by 45 percent. They credited the effects to canola oil and olive oil, the oils highest in oleic acid. To achieve optimum protection, 2 tablespoons per day is recommended.
It is still thought by most nutrition experts that one of the best ways to reduce the risk of breast cancer is to consume more omega-3 fatty acids. The protective effect of omega-3 fatty acids was first observed in Greenland Eskimo women who seemed to have a strikingly low rate of breast cancer. These women have a diet that is probably the highest in omega 3 fats of any group of women in the world. Laboratory, animal and epidemiological studies almost universally show reductions in breast cancer associated with high omega 3 fish oils. Fats containing high amounts of omega 3 polyunsaturated fats have been reported to have a suppressive effect on tumor growth in female rats as well as other animal models that have been studied. Fish that are generally available and contain high amounts of omega 3 oils include salmon, tuna, halibut, mackerel, sardines and herring.
It may be that the kinds of fats have more to do with breast cancer protection than the amount of fat. It has been difficult to conclusively associate amount or kinds of fat with breast cancer risk because there are many confounding nutritional variables in diets associated with low rates of breast cancer. One of these variables is fiber.
With all the attention on fat, fiber has been underrated as a breast cancer prevention strategy. A low fat diet, rich in insoluble fiber, has been shown to decrease the circulation of estrogens between the intestines and the liver and decrease plasma estrogen levels, thereby potentially reducing the risk of hormone-related cancers. Seeds and whole grains contain significant amounts of lignans. Once lignans are absorbed, they interfere with estrogenic activity and have a weak estrogen blocking effect on the breast. Breast cancer patients excrete lower levels of urinary lignans than healthy women do. The lack of sufficient lignans in the urine is in part due to a low-fiber diet. Vegetarians eat more fiber and more lignans than do non-vegetarians, and vegetarians excrete a high level of lignans. Vegetarians with a high lignan diet do in fact appear to have lower rates of breast cancer. Studies on dietary fiber have however yielded conflicting results. In one of the more recent analyses in June 1998, the International Journal of Cancer published the results of a study of 10,000 women with cancer, who were compared to 8,000 controls without the disease. The investigators concluded that a high intake of whole grain foods consistently reduced the risk of cancer at all sites, except thyroid. The importance of fiber-rich foods in the prevention of breast cancer should not be ignored, although proof of this effect is not yet conclusive.
Other nutritional influences such as diets high in carotenoids, vitamin C, fruits and vegetables, and soy intake also appear to be related to decreasing breast cancer risk. Soy isoflavones remains the subject that still deserves special consideration.
In countries like China, Thailand and Japan, soy foods have been a significant part of a traditional diet. With their low rates of breast cancer, prostate cancer, and numerous other chronic degenerative illnesses, a great deal of interest has developed around possible preventive nutrients in their diet. Over the last several years, natural food stores, and now even mass market grocery stores, have exploded in the availability of soy products due to a shift in attitude towards soy among many Americans… and for good reason. Soy foods are high in protein (38%), contain all the essential amino acids, are low in fat (18%), and contain primarily polyunsaturated fats. Many soy foods are also a good source of calcium. Perhaps soy’s biggest attention getting moment happened in 1999 when the FDA and the American Heart Association endorsed soy as being able to lower cholesterol and thereby reduced the risk of heart disease. Numerous menopause studies on hot flashes have also been promising in the ability of soy to reduce hot flashes. Other studies have found some evidence that soy consumption might help prevent the bone loss associated with menopause.
Isoflavones are plant compounds found mostly in legumes (soy, peas, beans, lentils, etc.). They are part of a larger class of compounds called phytoestrogens. Soybeans and soy products are the most common food sources of isoflavones and are high in two dominant isoflavones, genistein and daidzein. Additional isoflavones can be found in many other medicinal and edible plants such as red clover, which also contains formonenetin and biochanin.
When looking at the incidence of breast cancer around the world, one can easily take note that the mortality rate due to breast cancer is much lower in Asian countries where soy foods are consumed in much greater amounts than in the United States. In Japan, the breast cancer mortality rate is about one-quarter of that in the Unites States. It is also estimated that women in Japan eat between 30 mg and 80 mg of soy isoflavones daily where as in the U.S. it is an average of less than 1 mg. The evidence regarding breast cancer risk comes from in vitro evidence, animal studies and epidemiological evidence.
In vitro studies have consistently demonstrated that isoflavones are weakly estrogenic by weakly binding to estrogen receptors in mammals. Genistein has the greatest binding affinity but is still about 100 times less than estradiol, and daidzein is about 1000 times less. Their unique quality is that they bind to the receptor, but they do not stimulate a full estrogenic response and thereby they are able to act as both estrogens and anti-estrogens.
The mechanism by which isoflavones inhibit cancer cell growth is not fully understood but the following have been observed: antioxidant properties, inhibition of several enzyme systems involved in signal transduction (including tyrosine kinase), inhibition of angiogenesis, increasing sex hormone binding globulin, as well as the anti-estrogenic mechanism have all been observed. There are hundreds of studies demonstrating that genistein inhibits the growth of hormone-dependent and hormone-independent cancer cells.
With all of this reassurance, one study in particular has been disturbing. It showed that in a culture of a breast cancer cell line of estrogen sensitive breast cancer cells, when genistein was added in low doses, it stimulated cell division and replication of the breast cancer cells. However, when higher doses of genistein were added, growth was inhibited. What has been difficult to discern is what determines a low dose of isoflavones versus a high dose in humans. Dr. Bob Arnot in his book, The Breast Cancer Prevention Diet, recommends that in order to get high doses, one needs to eat between 35 to 60 grams per day of soy protein. This translates to between 35 mg and 120 mg of soy isoflavones per day (1 gram of soy protein contains between 1-2 mg of soy isoflavones).
The few epidemiological studies that have been done on the association of isoflavone intake and breast cancer risk indicated that populations of women who have a diet high in isoflavones have a reduced breast cancer risk and that ethnic groups who traditionally had a high isoflavone diet and then adopt a Western diet and lifestyle have an increased incidence in breast cancer. There have been four case-control studies of breast cancer and dietary isoflavone intake since 1990, two in China, one in Japan, and one study of Asian Americans (Chinese, Japanese and Filipino) in San Francisco, Los Angeles county and Hawaii. The sample size in Japan was the largest. In one of the studies in China, no association between the intake of soy and risk of breast cancer was seen in both pre and postmenopausal women. In the second study conducted in Singapore, high intake of soy was associated with a reduction in risk in premenopausal women but not in postmenopausal women. Premenopausal women who consumed greater that 55 grams of a soy product showed a 60% reduced risk compared with those who consumed less than 20 grams of soy per day.
In Japan, a high intake of bean curd was associated with a statistically insignificant reduction in the risk of pre menopausal breast cancer but not in postmenopausal women. There was no association with miso soup intake in either premenopausal or postmenopausal women. In the Asian-American study, tofu intake was associated with a lower risk of breast cancer in both pre -and postmenopausal women. In those who consumed tofu more than 120 times per year, a 30% reduction in risk was observed compared with women in the group who consumed tofu less than 12 times per year.
In looking at these four case-control studies, some evidence does exist showing as association between soy intake and the risk of breast cancer, but unfortunately, overall, the results are not definitive. One explanation is that the adjustment for dietary factors was not identical between these studies, and all case-control studies of diet and cancer are problematic in the methodology.
Two studies to date have looked at the levels of isoflavones or the metabolic end products in bodily fluids. In examining isoflavone and metabolite excretion such as equol, an increase in equol excretion was associated with the relative decreased risk of breast cancer. A similar effect was seen with enterolactone, a metabolite of lignan. A preliminary study in 2000, in postmenopausal women versus controls found that those with breast cancer had lower 24-hour urinary daidzein excretion than controls and a similar trend was observed with genistein excretion.
Additional convincing evidence for the breast cancer protection benefit of soy comes from animal studies. Soy supplementation has reduced the number and size of tumors that were induced with a carcinogenic substance. A review paper of 26 animal studies of experimental carcinogenesis in which diets containing soy or soybean isoflavones were employed, 17 reported protective effects. No studies reported soy intake increased tumor development.
Additional effects of isoflavones on hormones and breast cancer
Breast cancer risk has also been looked at by studying the effect of isoflavones on hormone levels. Theoretically, a reduction in serum hormone levels, a lengthened menstrual cycle, and a change to less carcinogenic metabolites could be related to breast cancer risk. A number of studies have examined hormonal endpoints. Consumption of an isoflavone-rich soy product showed that the length of the follicular phase was increased and therefore the menstrual cycle lengthened, as well as a decrease in follicle-stimulating hormone and luteinizing hormone. It has also been observed that breast cancer patients appear to have shorter menstrual cycles than controls; and Asian women have a longer cycle than Western women, who have higher rates of breast cancer. Women who have short menstrual cycles will, over the course of their lifetime, have more of their reproductive life in the luteal phase. The mitotic rate for breast tissue is almost fourfold greater during the luteal phase than during the follicular phase. If soy isoflavones can increase the length of the follicular phase, it may be able to reduce the risk of breast cancer.
Another issue that has promising implications is how isoflavones can increase the metabolism of endogenous estrogens to an anti-carcinogenic metabolite. Higher levels of 4 and 16 alpha-hydroxyestrogen (carcinogenic metabolites) and lower amounts of 2-hydroxyestrogen ( an anti-carcinogenic metabolite) have been associated with a greater risk of breast cancer. When supplemented with an isoflavone rich soy milk versus an isoflavone-free soy milk, higher levels of the anti-carinogenic 2-hydroxyestrogen was found in the urine. Also, the ratio of 2-hydroxyestrone to 16 alpha-hydroxyestrone (a carcinogenic metabolite) was higher during the isoflavone-rich diet than during the isoflavone-free diet.
Another study that offers some insight evaluated the effects of soy consumption on steroid hormones in premenopausal women. Six healthy women in their 20′s ingested 12 oz of soy milk three times daily for one month. Daily isoflavone intakes were approximately 100 mg of daidzein and 100 mg of genistein. Serum estradiol levels decreased by 31% on cycle days 5-7, 12-14 and 20-22. Progesterone levels in the second half of the cycle decreased by 35%. Menstrual cycle length extended from 28.3 days to 31.8 days during the one month of soy. These results suggest that consumption of soy diets containing phytoestrogens may reduce circulating ovarian steroids, increase menstrual cycle length, two effects that may account in part for decreased risk of breast cancer.
Not all is positive however, and two studies have shown that soy may exert estrogenic effects on breast tissue. In premenopausal women, the rate of DNA synthesis by breast cells taken from normal breast tissue in women who had either benign or malignant disease, was increased by giving 14 days of 45 mg of isoflavones. The second report is from studying the nipple aspirate of 50 premenopausal women who are at high risk for breast cancer. The women had 3 months of a diet free of soy, with samples taken of their nipple fluid, blood, and urine. They then incorporated into their diet two servings a day of a soy based nutritional beverage powder for 12 months. The 38 grams of soy protein consumed each day contained 70 mg of genistein. Samples were taken at 3 month intervals. The report to date is that the soy increased the nipple aspirate fluid and increased the number of atypical cells in the fluid. This may be a marker for substances that might increase breast cancer risk , although certainly not considered a diagnostic indicator.
There is a legitimate question to be raised regarding the safety of soy when it comes to women who have or have had breast cancer. Is it safe? And, is it different for premenopausal women than for postmenopausal women with a breast cancer history?
Premenopausal women normally have higher estrogen levels than postmenopausal women who are not on hormone replacement therapy. In premenopausal women who eat a diet or take supplements high in phytoestrogens, these weak plant compounds stimulate estrogen receptors and perform some of the same functions as our own body’s stronger estrogens. Our chemical messenger system then says we already have enough total estrogen here, therefore the ovaries produce less estrogen because more is not needed. By doing this, the rate of production of the body’s stronger estrogen declines, and the total estrogen effect on the body (lower internal estrogen production plus weak plant phytoestrogens) is now lower. This mechanism is in part what earns phytoestrogens the characteristic of being called both a “proestrogen” and an “antiestrogen”.
With postmenopausal women, the result of these mechanisms may be different. Postmenopausal women produce less estrogen, and the total level is low. Eating a high phytoestrogen diet or soy supplement boosts the total estrogen levels, even though these estrogens are far weaker. Now, it would seem that because we have a higher total estrogen effect, it may affect the breast differently when the breast is prepared for less estrogen stimulation at this time in life. The problem is this. We have many facts about women who eat soy throughout their lifetime starting at an early age. We have animal studies and laboratory studies about the mechanisms and the anti-tumor effects of soy. But, what we don’t have yet is a large body of information on women who begin taking large amounts of soy later in life starting after menopause; and we don’t have information on the effects of soy in women who have had breast cancer.
Tamoxifen and Soy
Breast cancer patients, especially if they are postmenopausal with estrogen receptor positive tumors, are often recommended the anti-estrogen drug, tamoxifen. Genistein has been shown to exert antagonistic and antiproliferative actions in mammary tissues, as we have discussed. However, at lower concentrations, genistein may be able to act as an agonist in estrogen-dependent target cells and promote estrogen-receptor positive breast cancer cell proliferation. In one in vitro study, the anti-estrogen effect of tamoxifen on breast cancer cell lines was altered by and the steroid receptor interfered with by low levels of genestein. These findings are consistent with another study which showed that tamoxifen was unable to block DNA synthesis induced by low levels of genistein in breast cancer cells lines. Other tamoxifen studies have been of less concern and do not show the antagonistic effect of genistein. Until further research however, it appears to be prudent to advise women on tamoxifen to avoid soy.
Doubts as to the significance of the breast cancer protective effects of soy and the safety of soy in breast cancer patients will remain. Until there has been a prospective study on soy comparing women on a high soy diet with women on a no soy diet over the span of many years with identical risk factors in other areas will we be able to advise with absolute confidence. Perhaps more importantly, long term prospective studies with breast cancer patients comparing high and no soy diets will be the final chapter in understanding the facts.
As a practitioner who advises women as to their health care decisions concerning breast cancer, I have had to come to some decision about this now while waiting for more scientific information to unfold. Here is what I tell my patients:
- We have evidence that women who eat high soy diets during their lifetime have significantly less breast cancer.
- We know that soy phytoestrogens are significantly weaker than estradiol.
- Phytoestrogens compete with estradiol for the binding of estrogen receptor sites thereby blocking stronger estrogens from binding there.
- A review of most of the biological effects, the mechanisms of action and metabolism of soy, along with the epidemiologic and animal studies suggests that soy phytoestrogens provide cancer protection.
- We also have seen soy inhibit tumor growth in animal studies.
- Epidemiological trials in humans have reported a protective effect of soybean products against the development of breast cancer.
- The phytoestrogen mechanism of soy isoflavones is overshadowing all of the other clear anti cancer mechanisms of soy: inhibiting enzyme systems, anti-angiogenesis, inhibition of free radicals, and increasing antioxidant enzymes.
- Eat more than 70 mg of soy isoflavones daily, even more for breast cancer patients.
- Use soy isoflavone supplements in the range of 100-200mg of isoflavones in addition to soy protein in the diet daily.
- Breast cancer patients who are suffering from menopausal symptoms are given hormone replacement therapy (HRT) – it is believed that the risk of a cancer recurrence is small and may even reduce metastasis, and that the quality of life issues and benefits of HRT are greater than the risk of HRT. When comparing the strength of HRT to the strength of soy isoflavones, this decision to take hormone support for quality of life becomes even more poignant.
- Avoid soy if on tamoxifen
These studies and clinical observations give me great reassurance not only as to the benefit of soy for breast cancer survivors, but to the safety of soy as well. Looked at in another way, the benefits of soy in the areas of hot flashes, vaginal dryness, cholesterol lowering, and bone density may outweigh any speculative potential risk. We must, however, continue to keep an open mind and extend our science and our scrutiny to the benefits as well as the potential risks. And always, treat each patient individually. What may be a good recommendation and benefit one woman, may be an inappropriate recommendation and do harm, in another. Treat the person, not the disease. Weigh the benefits and the risks for each individual.
- Miller A, Berrino F, Hill M, et al. Diet in the etiology of cancer: a review. Eur J Cancer 1994;30A:207-220.
- Carroll K, et al. Dietary fat and mammary cancer. Can Med Assoc J 1968;98:590-593.
- Willett W, et al. Dietary fat and fiber in relation to risk of breast cancer. JAMA 1992;268:2037-2044.
- Holmes M, Hunter D, Colditz G, et al. Association of dietary intake of fat and fatty acids with risk of breast cancer. JAMA 1999;281:914-920.
- Trichopoulou An, Katsouyanni K, Stuver S, et al. Consumption of olive oil and specific food groups in relation to breat cancer risk in Greece. J NCI 1995;87(2):110-115.
- Wolk A, et al. A prospective study of association of monounsaturated fat and other types of fat with risk of breast cancer. Arch Intern Med 1998;158(1):41-45.
- Tang B, Adams N. Effect of equal on estrogen receptors and on synthesis of DNA and protein in the immature rat uterus. J Endocrinol 1980;85:291-297.
- Messina M. Legumes and soybeans: overview of their nutritional profiles and health effects. Am J Clin Nutr 1999; 70:439S-450S.
- Zava D, Duwe G. Estrogenic bioactivity of phytoestrogens in human breast cancer cells in monolayer culture. California Public Health Foundation, Cancer Research Division and Aeron Biotechnology, Inc.
- Adlercreutz H. Western diet and Western diseases: some hormonal and biochemical mechanisms and associations. Scand J Clin Lab Invest Suppl 1990;201:3-23.
- Ingram D, Sander K, Kolybaba M, Lopez D. Case-control study of phyto-oestrogens and breast cancer. Lancet 1998;350:990-994.
- Wu A, Ziegler R, Nomura A, et al. Soy intake and risk of breast cancer in Asians and Asian Americans. Am J Clin Nut 1998;68:1437S-1443S.
- Buell P. Changing incidence of breast cancer in Japanese American women. J Natl Cancer Inst 1973;51:1479-1483.
- Lee H, Day N, Shanmugaratnam K. Trends in cancer incidence in Singapore 1968-1982. IARC Sci Publ 1988;1-161.
- Yuan J, Wang Q, Ross R, et al. Diet and breast cancer in Shanghai and Tianjin, China. Br J Cancer 1995;71:1353-58.
- Lee H, Gourley L, Duffy S, et al. Dietary effects on breast cancer risk in Singapore. Lancet 1991;337:1197-1200.
- Lee H, Gourley L, Duffy S, et al. Risk factors for breast cancer by age and menopausal status: a case-control study in Singapore. Cancer Causes Control 1992;3:313-322.
- Hirose K, Tajima K, Hamajima N, et al: A large-scale, hospital based case-control study of risk factors of breast cancer according to menopausal status. Jpn J Cancer Res 1995;86:146-154.
- We A, Ziegler R, Horn-Ross P, et al. Tofu and risk of breast cancer in Asian-Americans. Cancer Epidemiol Biomarkers Prev 1996 1996;5:901-906.
- Ingram D, Sander K, Kolybaba M, Lopez D. Case-control study of phto-oestrogens and breast cancer. Lancet 1998;350:990-994.
- Messina M, Barnes S, Setchell K: Phyto-oestrogens and breast cancer. Lancet 1997;350:971-972.
- Murkies A, Dalais F, Briganti E, et al. Phytoestrogens and breast cancer in postmenopausal women: a case control study. Menopause 2000;7:289-296.
- Barnes S, Peterson G, Grubbs C, Setchell K. Potential role of dietary isoflavones in the prevention of cancer. In Jacobs MM, ed. Diet and Cancer: Markers, Prevention, and Treatment. New York: Plenum Press, 1994:135-147.
- Bingham S, Atkinson C, Liggins J, Bluck L, Coward A. Phyto-oestrogens: where are we now? Br J Nutr 1998;79:393-406.
- Cassidy A, Bingham S, Setchell K. Biological effects of a diet of soy protein rich in isoflavones on the menstrual cycle of premenopausal women. Am J Clin Nutr 1994;60:333-340.
- Cassidy A, Bingham S, Setchell K: Biological effects of isoflavones in young women: importance of the chemical composition of soyabean products. Br J Nutr 1995;74:587-601.
- Olsson H, Landin-Olsson M, Gullberg B. Retrospective assessment of menstrual cycle length in patients with breast cancer, in patients with benign breast disease, and in women without breast disease. J Natl Cancer Inst 1983;70:17-20.
- Lu L, Cree M, Josyula S, et al. Increased urinary excretion of 2-hydroxyestrone but not 16 alpha-hydroxyestrone in premenopausal women during a soya diet containing isoflavones. Cancer Res 2000;60:1299-1305.
- Lu L, Anderson K, Grady J, et al. Cancer Epidemiol Biomarkers Prev 1996;5:63-70. Effects of soya consumption for one month on steroid hormones in premenopausal women: implications for breast cancer risk reduction.
- McMichael-Phllips D, Harding C, Morton M, et al. Effects of soy-protein supplementation on epithelial proliferation in the histologically normal human breast. Am J Clin Nutr 1998;68:1431S-1435S.
- Petrakis N, Wiencke J, et al. A clinical trial of the chemopreventive effect of a soy beverage in women at high risk for breast cancer. Department of Epidemiology, University of California San Fancisco, SF, CA and Department of Pharmacology, University of Alabama at Birmingham, AL.
- Schwartz J, Gouzhen L, Brooks S. Genistein-Mediated Attenuation of Tamoxifen-Induced Antagonism from Estrogen Receptor-Regulated Genes. Biochemical and Biophysical Research Comm 1998;253:38-43.
- Wang C, Kurzer M. Nutr Cancer 1998;31:90-100