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Eating to beat breast cancer: Potential role for soy supplements
Annals of Oncology 8 223-225, 1997. © 1997 Klim er Academic Publishers Printed in the Netherlands.
Special article Eating to beat breast cancer: Potential role for soy supplements B. A. Stoll Oncology Department, St. Thomas' Hospital, London, UK
Summary
Background: The study reviews the anticancer properties of natural isoflavones which occur in especially high concentration in soybeans. It considers the suitability of soybean products for clinical trials aiming to reduce the progression of breast cancer. Methods: Evidence is reviewed that plant isoflavones such as genistein show cytostatic activity against human mammary cancer cell lines in vitro and can also suppress carcinogeninduced mammary cancer in young and mature rats. Results: Plant isoflavones are converted in the bowel to compounds with potential antioestrogenic and antioxidative properties. These compounds show cytostatic activity for both
Introduction
Compelling evidence that fresh vegetables and fruit can protect against cancer was presented at a recent symposium of the American Association for Cancer Research in Washington [1]. Participants advised that second generation dietary supplement trials needed to be planned, even though the first group of vitamin and mineral studies are not yet completed. In the case of breast cancer, multiple reports have shown a decreased risk in association with a high dietary intake of vegetable or fruit fibre (reviewed in [2]), but trials aiming to identify the specific protective agents are limited by the absence of a reliable molecular marker of early malignant change in breast tissue. One way forward is to test dietary supplements known to contain cancer-restraining agents in early breast cancer patients by long-term adjuvant treatment after primary surgery. Using a protocol similar to that used in the Milan vitamin A analogue trials [3], delay in recurrence and reduction of second primary growths can be looked for.
Anticancer properties of isoflavones Soybeans are rich in isoflavones which are converted in the bowel to compounds with antiproliferative properties. Soy fractions which contain genistein have been shown to inhibit the growth of various animal tumours
oestrogen receptor-positive and negative human mammary cancer cell lines, and also inhibit growth and progress of the rat mammary cancer model. The high content of soybean products in the diet of Asian women has been postulated as one reason for their relatively low breast cancer incidence. Conclusion: Preclinical studies suggest that soybean products be given priority for clinical trials in breast cancer protection. A pilot study could test soy protein supplements as longterm adjuvant dietary treatment after primary surgery for early breast cancer, looking for a decrease in the risk of recurrence or of second primary tumours. Key words: breast cancer, diet, genistein, isoflavones, soybean, tyrosine kinase
including mammary, prostate, colon, bladder, liver, lung and skin cancers [4]. In the case of mammary tumours, genistein-containing soy fractions inhibit the growth of carcinogen-induced mammary cancer in both adult and prepubertal rats [5]. In addition, they inhibit the growth of additional tumours which often appear after excision of the primary mammary tumour [6]. Isoflavones also exert a cytostatic effect on several cell lines derived from human mammary cancer [7]. Genistein is the most active of the isoflavones in this respect but daidzein and equol are also effective. In addition, other components of soy fractions, such as phytic acid and protease inhibitors have shown growthinhibitory properties [7]. While isoflavones are most abundant in legumes such as soybeans and chickpeas, they are also present in cereals, seeds, and fruits, and both naringenin and hesperetin found in oranges and grapefruit, have been shown to inhibit the growth of human breast cancer cell lines [8]. Soy protein is present in more than half of Western supermarket food products and its use is increasing. Modern soy products are bland in flavour and are processed into chocolate, cooking oils, milk drinks, pasta, sausage, breakfast cereals, desserts and precooked meals, or sold as soy drinks, tofu, soy flour and soy flakes. In spite of this, the Westerner's intake of isoflavones is still less than 5 mg daily compared with 20 to 80 mg for Asians [7]. In Japan and China, where the incidence of breast cancer is one fifth of that in
224 Western women, soy protein is a major dietary component. A Japanese prospective study found an inverse relationship between breast cancer risk and intake of miso soup, although a case-control study has failed to show a protective effect from soy intake [9]. A casecontrol study of Chinese women in Singapore found an inverse association between breast cancer risk and soy protein intake in premenopausal women [10] but a more recent Chinese study showed no such association [11]. Isoflavones have a weak oestrogenic activity, but antioestrogenic properties are also reported [12]. Genistein at high concentration inhibits the growth of receptorpositive human breast cancer cell lines, although at lower concentrations growth is stimulated [13]. Isoflavones are thought to compete with oestradiol for binding to oestrogen receptor, and prolonged exposure decreases the response of cancer cells to oestrogen stimulation [14]. A recent study in premenopausal women [15] reported that administration of soy milk supplements of over 200 mg isoflavone daily for one month caused reduction of serum oestradiol levels which persisted for two to three months after soy was withdrawn. On the other hand, an earlier study in premenopausal women [16] reported that soy supplements of 45 mg isoflavone daily caused a rise in oestradiol levels. It is possible that beyond a threshold intake, genistein may decrease ovarian aromatisation of androgen to oestrogen by inhibiting tyrosine kinases in ovarian follicular cells [17]. Most studies assume that the antiproliferative effect of genistein in mammary cancer involves an effect on oestrogen bioactivity, but at high concentration it also inhibits the growth of oestrogen receptor-negative human breast cancer cell lines [13]. It has been shown to inhibit growth stimulation in these cells induced by insulin or insulin-like growth factor [14, 18]. Activity of these growth factors is mediated by IGF1 receptor tyrosine kinase activity and the cancerostatic effect of genistein may be exerted by blocking this process [18]. However, genistein's antioxidant properties may also contribute to its cancer-restraining effect in non hormone-related cancers [19]. Many agents are competing for selection in human cancer chemoprevention trials. An agent that can be given orally, is free from any potential side effect and has compelling animal and laboratory evidence of cancerostatic properties should be given high priority. The safety of food derived from soybeans is assured by a history of its wide use for centuries in Asian populations. Allergic reactions to soy products are rare in adults. Although soy products may have a relatively low zinc, iron and calcium content, their incorporation into a well balanced diet should avoid problems [20]. An added advantage of soy protein is that it reduces blood lipid levels and has been shown effective in treating hypercholesterolaemia [21]. The mechanism and component of soy responsible for this effect is uncertain but may be related to the isoflavone content [22].
Proposal for clinical study Because of its confirmed effect on the mammary cancer model in rats and also on human mammary cancer cell lines, soy protein appears to be suitable for clinical trial to assess a possible effect in arresting or reversing breast cancer progression in the human. The first clinical trials could involve its long-term administration as adjuvant management after primary surgery in women with early breast cancer. Patients would be randomised into intervention and control groups, and compared for the incidence of recurrence and second primary breast cancer. The latter may provide evidence of a cancer-preventive effect as has been suggested in current adjuvant trials of tamoxifen and retinoid analogues in early breast cancer cases. Monitoring of weight, sex-steroid and metabolic parameters would be incorporated in the trial. A clinical trial should aim at an isoflavone intake of at least 100 mg daily and this should not be difficult to achieve. Processing techniques have created a new generation of soy flour extracts with mild flavour and aroma, which can be incorporated into a wide variety of food products. These include mixtures of soy protein with cereals, dried milk or dried egg, apart from the traditional soy foods such as tofu and soy drinks which have the highest isoflavone content. Conclusion Further studies are required to investigate the effect of plant isoflavones on non-transformed mammary cells [7], but there is enough evidence to warrant the setting up of trials of soy protein supplement as adjuvant treatment following primary surgery for early breast cancer. Not only is a diet containing soybean supplements completely safe and palatable, but in addition it would satisfy the desire of many patients to use a natural treatment and play an active role themselves in their fight against disease.
References 1. AACR Symposium. Nutrition and cancer. J Natl Cancer Inst 1996; 88: 947-9. 2. Stoll BA. Can supplementary dietary fibre suppress breast cancer growth? Br J Cancer 1996; 73: 557-9. 3 Veronesi U, De Palo G, Costa A et al. Chemoprevention of breast cancer with retinoids. NCI Monogr 1992; 12: 93-7. 4. Messina M, Barnes S. The role of soy products in reducing risks of certain cancers. J Natl Cancer Inst 1991; 83: 941-6. 5. Lamartiniere CA, Moore JB, Brown NM et al. Genistein suppresses mammary cancer in rats. Carcinogenesis 1995; 16: 2833-40. 6. Hawrylewicz EJ, Zapata JJ, Blair WH. Soy and experimental cancer: Animal studies. J Nutr 1995; 125 (Suppl 3): S698-708. 7. Barnes S. Effect of genistein on in vitro and in vivo models of cancer. J Nutr 1995; 125 (Suppl 3): S777-S3. 8. So FV, Guthrie N, Chambers AF et al. Inhibition of human breast cancer cell proliferation and delay of mammary tumongenesis by flavonoids and citrus juices. Nutr Cancer 1996; 26: 167-81.
225 9. Perksby V, van Horn L. Epidemiology of soy and cancer: Perspectives and directions. J Nutr 1995; 125 (Suppl 3). S709-12. 10. Lee HP, Gouriey L, Duffy SW et al. Dietary effects on breast cancer risk in Singapore. Lancet 1991; 337: 1197-200. 11. Yuan JM, Wang QS, Ross PK et al. Diet and breast cancer in Shanghai and Tianjin, China. Br J Cancer 1995; 71: 1353-8. 12. Adlercreulz H. Diet, breast cancer and sex hormone metabolism. Ann NYAcad Sci 1990; 595: 281-90. 13. Wang TT, Sathyamoorthy N, Phang JM. Molecular effects of genistein on estrogen receptor mediated pathways. Carcinogenesis 1996; 17: 271-5. 14. Hoffman R. Potent inhibition of breast cancer cell lines by the isoflavonoid kievitone. Comparison with genistein Biochem Biophys Res Commun 1995; 211: 600-6. 15. Lu LJW, Anderson K.E, Grady JJ, Nagamani M. Effects of soya consumption for one month on steroid hormones in premenopausal women: Implications for breast cancer nsk reduction. Cancer Epidemial Biomarkers Prev 1996, 5: 63-70. 16. Cassidy A, Bingham S, Setchell K. Biological effects of isoflavones in young women1 Importance of the chemical composition of soyabean products. Br J Nutr 1995; 74: 587-601. 17. GangTade BK, Davis JS, May J U Induction of aromatase in
18.
19.
20. 21.
22.
ovarian cells in vino: Role of TGFa-induced tyrosine kinase. Endocrinology 1991; 129: 2790-2. Pagliacci MG, Smacchia M, Miglionati G et al. Growth-inhibitory effects of the natural phyto-oestrogen genistein in MCF7 human breast cancer cells. Eur J Cancer 1994; 30A: 1675-82. Wei H, Bowen R, Cai Q et al. Antioxidant and antipromotional effects of the soybean isoflavone genistein. Proc Soc Exp Biol Med 1995; 208: 124-30. Erdman JW. Control of serum lipids with soy protein. N Engl J Med 1995; 333: 313-4. Anderson JW, Johnstone BM, Cook-Newell ME. Meta-analysis of the effects of soy protein intake on serum lipids. N Engl J Med 1995; 333: 276-82. Potter SM. Overview of proposed mechanics for the hypocholesterolemic effect of soy. J Nutr 1995; 125 (Suppl 3): S606-11.
Received 8 November 1996; accepted 18 December 1996. Correspondence to: Dr. Basil A. Stoll, FRCR Oncology Department, St Thomas' Hospital London SE1 7EH, UK
Special article Eating to beat breast cancer: Potential role for soy supplements B. A. Stoll Oncology Department, St. Thomas' Hospital, London, UK
Summary
Background: The study reviews the anticancer properties of natural isoflavones which occur in especially high concentration in soybeans. It considers the suitability of soybean products for clinical trials aiming to reduce the progression of breast cancer. Methods: Evidence is reviewed that plant isoflavones such as genistein show cytostatic activity against human mammary cancer cell lines in vitro and can also suppress carcinogeninduced mammary cancer in young and mature rats. Results: Plant isoflavones are converted in the bowel to compounds with potential antioestrogenic and antioxidative properties. These compounds show cytostatic activity for both
Introduction
Compelling evidence that fresh vegetables and fruit can protect against cancer was presented at a recent symposium of the American Association for Cancer Research in Washington [1]. Participants advised that second generation dietary supplement trials needed to be planned, even though the first group of vitamin and mineral studies are not yet completed. In the case of breast cancer, multiple reports have shown a decreased risk in association with a high dietary intake of vegetable or fruit fibre (reviewed in [2]), but trials aiming to identify the specific protective agents are limited by the absence of a reliable molecular marker of early malignant change in breast tissue. One way forward is to test dietary supplements known to contain cancer-restraining agents in early breast cancer patients by long-term adjuvant treatment after primary surgery. Using a protocol similar to that used in the Milan vitamin A analogue trials [3], delay in recurrence and reduction of second primary growths can be looked for.
Anticancer properties of isoflavones Soybeans are rich in isoflavones which are converted in the bowel to compounds with antiproliferative properties. Soy fractions which contain genistein have been shown to inhibit the growth of various animal tumours
oestrogen receptor-positive and negative human mammary cancer cell lines, and also inhibit growth and progress of the rat mammary cancer model. The high content of soybean products in the diet of Asian women has been postulated as one reason for their relatively low breast cancer incidence. Conclusion: Preclinical studies suggest that soybean products be given priority for clinical trials in breast cancer protection. A pilot study could test soy protein supplements as longterm adjuvant dietary treatment after primary surgery for early breast cancer, looking for a decrease in the risk of recurrence or of second primary tumours. Key words: breast cancer, diet, genistein, isoflavones, soybean, tyrosine kinase
including mammary, prostate, colon, bladder, liver, lung and skin cancers [4]. In the case of mammary tumours, genistein-containing soy fractions inhibit the growth of carcinogen-induced mammary cancer in both adult and prepubertal rats [5]. In addition, they inhibit the growth of additional tumours which often appear after excision of the primary mammary tumour [6]. Isoflavones also exert a cytostatic effect on several cell lines derived from human mammary cancer [7]. Genistein is the most active of the isoflavones in this respect but daidzein and equol are also effective. In addition, other components of soy fractions, such as phytic acid and protease inhibitors have shown growthinhibitory properties [7]. While isoflavones are most abundant in legumes such as soybeans and chickpeas, they are also present in cereals, seeds, and fruits, and both naringenin and hesperetin found in oranges and grapefruit, have been shown to inhibit the growth of human breast cancer cell lines [8]. Soy protein is present in more than half of Western supermarket food products and its use is increasing. Modern soy products are bland in flavour and are processed into chocolate, cooking oils, milk drinks, pasta, sausage, breakfast cereals, desserts and precooked meals, or sold as soy drinks, tofu, soy flour and soy flakes. In spite of this, the Westerner's intake of isoflavones is still less than 5 mg daily compared with 20 to 80 mg for Asians [7]. In Japan and China, where the incidence of breast cancer is one fifth of that in
224 Western women, soy protein is a major dietary component. A Japanese prospective study found an inverse relationship between breast cancer risk and intake of miso soup, although a case-control study has failed to show a protective effect from soy intake [9]. A casecontrol study of Chinese women in Singapore found an inverse association between breast cancer risk and soy protein intake in premenopausal women [10] but a more recent Chinese study showed no such association [11]. Isoflavones have a weak oestrogenic activity, but antioestrogenic properties are also reported [12]. Genistein at high concentration inhibits the growth of receptorpositive human breast cancer cell lines, although at lower concentrations growth is stimulated [13]. Isoflavones are thought to compete with oestradiol for binding to oestrogen receptor, and prolonged exposure decreases the response of cancer cells to oestrogen stimulation [14]. A recent study in premenopausal women [15] reported that administration of soy milk supplements of over 200 mg isoflavone daily for one month caused reduction of serum oestradiol levels which persisted for two to three months after soy was withdrawn. On the other hand, an earlier study in premenopausal women [16] reported that soy supplements of 45 mg isoflavone daily caused a rise in oestradiol levels. It is possible that beyond a threshold intake, genistein may decrease ovarian aromatisation of androgen to oestrogen by inhibiting tyrosine kinases in ovarian follicular cells [17]. Most studies assume that the antiproliferative effect of genistein in mammary cancer involves an effect on oestrogen bioactivity, but at high concentration it also inhibits the growth of oestrogen receptor-negative human breast cancer cell lines [13]. It has been shown to inhibit growth stimulation in these cells induced by insulin or insulin-like growth factor [14, 18]. Activity of these growth factors is mediated by IGF1 receptor tyrosine kinase activity and the cancerostatic effect of genistein may be exerted by blocking this process [18]. However, genistein's antioxidant properties may also contribute to its cancer-restraining effect in non hormone-related cancers [19]. Many agents are competing for selection in human cancer chemoprevention trials. An agent that can be given orally, is free from any potential side effect and has compelling animal and laboratory evidence of cancerostatic properties should be given high priority. The safety of food derived from soybeans is assured by a history of its wide use for centuries in Asian populations. Allergic reactions to soy products are rare in adults. Although soy products may have a relatively low zinc, iron and calcium content, their incorporation into a well balanced diet should avoid problems [20]. An added advantage of soy protein is that it reduces blood lipid levels and has been shown effective in treating hypercholesterolaemia [21]. The mechanism and component of soy responsible for this effect is uncertain but may be related to the isoflavone content [22].
Proposal for clinical study Because of its confirmed effect on the mammary cancer model in rats and also on human mammary cancer cell lines, soy protein appears to be suitable for clinical trial to assess a possible effect in arresting or reversing breast cancer progression in the human. The first clinical trials could involve its long-term administration as adjuvant management after primary surgery in women with early breast cancer. Patients would be randomised into intervention and control groups, and compared for the incidence of recurrence and second primary breast cancer. The latter may provide evidence of a cancer-preventive effect as has been suggested in current adjuvant trials of tamoxifen and retinoid analogues in early breast cancer cases. Monitoring of weight, sex-steroid and metabolic parameters would be incorporated in the trial. A clinical trial should aim at an isoflavone intake of at least 100 mg daily and this should not be difficult to achieve. Processing techniques have created a new generation of soy flour extracts with mild flavour and aroma, which can be incorporated into a wide variety of food products. These include mixtures of soy protein with cereals, dried milk or dried egg, apart from the traditional soy foods such as tofu and soy drinks which have the highest isoflavone content. Conclusion Further studies are required to investigate the effect of plant isoflavones on non-transformed mammary cells [7], but there is enough evidence to warrant the setting up of trials of soy protein supplement as adjuvant treatment following primary surgery for early breast cancer. Not only is a diet containing soybean supplements completely safe and palatable, but in addition it would satisfy the desire of many patients to use a natural treatment and play an active role themselves in their fight against disease.
References 1. AACR Symposium. Nutrition and cancer. J Natl Cancer Inst 1996; 88: 947-9. 2. Stoll BA. Can supplementary dietary fibre suppress breast cancer growth? Br J Cancer 1996; 73: 557-9. 3 Veronesi U, De Palo G, Costa A et al. Chemoprevention of breast cancer with retinoids. NCI Monogr 1992; 12: 93-7. 4. Messina M, Barnes S. The role of soy products in reducing risks of certain cancers. J Natl Cancer Inst 1991; 83: 941-6. 5. Lamartiniere CA, Moore JB, Brown NM et al. Genistein suppresses mammary cancer in rats. Carcinogenesis 1995; 16: 2833-40. 6. Hawrylewicz EJ, Zapata JJ, Blair WH. Soy and experimental cancer: Animal studies. J Nutr 1995; 125 (Suppl 3): S698-708. 7. Barnes S. Effect of genistein on in vitro and in vivo models of cancer. J Nutr 1995; 125 (Suppl 3): S777-S3. 8. So FV, Guthrie N, Chambers AF et al. Inhibition of human breast cancer cell proliferation and delay of mammary tumongenesis by flavonoids and citrus juices. Nutr Cancer 1996; 26: 167-81.
225 9. Perksby V, van Horn L. Epidemiology of soy and cancer: Perspectives and directions. J Nutr 1995; 125 (Suppl 3). S709-12. 10. Lee HP, Gouriey L, Duffy SW et al. Dietary effects on breast cancer risk in Singapore. Lancet 1991; 337: 1197-200. 11. Yuan JM, Wang QS, Ross PK et al. Diet and breast cancer in Shanghai and Tianjin, China. Br J Cancer 1995; 71: 1353-8. 12. Adlercreulz H. Diet, breast cancer and sex hormone metabolism. Ann NYAcad Sci 1990; 595: 281-90. 13. Wang TT, Sathyamoorthy N, Phang JM. Molecular effects of genistein on estrogen receptor mediated pathways. Carcinogenesis 1996; 17: 271-5. 14. Hoffman R. Potent inhibition of breast cancer cell lines by the isoflavonoid kievitone. Comparison with genistein Biochem Biophys Res Commun 1995; 211: 600-6. 15. Lu LJW, Anderson K.E, Grady JJ, Nagamani M. Effects of soya consumption for one month on steroid hormones in premenopausal women: Implications for breast cancer nsk reduction. Cancer Epidemial Biomarkers Prev 1996, 5: 63-70. 16. Cassidy A, Bingham S, Setchell K. Biological effects of isoflavones in young women1 Importance of the chemical composition of soyabean products. Br J Nutr 1995; 74: 587-601. 17. GangTade BK, Davis JS, May J U Induction of aromatase in
18.
19.
20. 21.
22.
ovarian cells in vino: Role of TGFa-induced tyrosine kinase. Endocrinology 1991; 129: 2790-2. Pagliacci MG, Smacchia M, Miglionati G et al. Growth-inhibitory effects of the natural phyto-oestrogen genistein in MCF7 human breast cancer cells. Eur J Cancer 1994; 30A: 1675-82. Wei H, Bowen R, Cai Q et al. Antioxidant and antipromotional effects of the soybean isoflavone genistein. Proc Soc Exp Biol Med 1995; 208: 124-30. Erdman JW. Control of serum lipids with soy protein. N Engl J Med 1995; 333: 313-4. Anderson JW, Johnstone BM, Cook-Newell ME. Meta-analysis of the effects of soy protein intake on serum lipids. N Engl J Med 1995; 333: 276-82. Potter SM. Overview of proposed mechanics for the hypocholesterolemic effect of soy. J Nutr 1995; 125 (Suppl 3): S606-11.
Received 8 November 1996; accepted 18 December 1996. Correspondence to: Dr. Basil A. Stoll, FRCR Oncology Department, St Thomas' Hospital London SE1 7EH, UK