This article was downloaded by: [University of Sussex Library] On: 25 March 2015, At: 15:12 Publisher: Routledge Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Nutrition and Cancer Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/hnuc20
Dietary fiber and breast cancer David P. Rose
a
a
Division of Nutrition and Endocrinology , American Health Foundation , 1 Dana Rd., Valhalla, NY, 10595 Published online: 04 Aug 2009.
To cite this article: David P. Rose (1990) Dietary fiber and breast cancer, Nutrition and Cancer, 13:1-2, 1-8, DOI: 10.1080/01635589009514040 To link to this article: http://dx.doi.org/10.1080/01635589009514040
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://www.tandfonline.com/page/ terms-and-conditions
Review
Dietary Fiber and Breast Cancer
Downloaded by [University of Sussex Library] at 15:12 25 March 2015
David P. Rose
Abstract Evidence from epidemiological studies suggests that dietary fiber, as well as fat, has the potential for affecting breast cancer risk. Fiber may have a protective role because of its influence on estrogen metabolism and excretion or because of the endocrine effects of the lignans, a family of compounds formed in the intestine from fiber-associated precursors. Future research should include additional mechanistic studies and dietary intervention trials in groups of women that have a high risk of breast cancer. (Nutr Cancer 13, 1-8, 1990)
Introduction
In general, international comparisons show both a strong positive correlation between the age-adjusted mortality rates for breast and colon cancers and an association between these two tumors and diets that are high in animal fats (1). In addition to wide acceptance for a protective effect of dietary fiber against colon cancer, which is supported by both epidemiological and experimental data (2), recent observations suggest that this proposed benefit of relatively high fiber intakes may also extend to breast cancer. One problem with performing epidemiological studies of diet and cancer risk is that in most human populations a high-fat intake is associated with a low-fiber intake and vice versa. An instructive exception exists in Finland. Here, dietary fat consumption is very high but so also is fiber intake. Moreover, while the United States, for example, has a high breast cancer mortality rate (the age-adjusted figure for 1978-1979 was 22.19/100,000), the risk for Finnish women is considerably less (14.87/100,000). A modifying influence of fiber on the breast cancer risk associated with high-fat intake may explain, at least in part, the lower incidence of this disease in Finland compared with the United States (3). Another difficulty in the case of fiber, to which insufficient consideration has been given in the past, is that the term includes a wide range of plant cell wall and interstitial components with distinct chemical and biological properties. D. P. Rose is affiliated with the Division of Nutrition and Endocrinology, American Health Foundation, Valhalla, NY 10595.
Copyright © 1990, Lawrence Erlbaum Associates, Inc.
Downloaded by [University of Sussex Library] at 15:12 25 March 2015
Epidemiological Studies
Case-control studies of diet and cancer are frequently handicapped by the homogeneity of dietary practices in a given population. Israel is one of several locations that, because of different cultural backgrounds within the same population, do provide a useful range of intakes of key nutrients. Lubin and co-workers (4), using state-of-the-art methodology, examined the relationships between dietary fat and fiber and breast cancer in that country. They found that a high-fat/low-fiber diet was associated with a doubling of breast cancer risk when a relative risk of 1.0 was assigned to those with the lowest fat and high fiber intakes. When the independent effects of the two dietary constituents were evaluated, fat had a strongly positive association with risk; increasing fiber intakes were negatively correlated with risk, although the relationship was not as strong as the positive one for dietary fat. An earlier study from Buffalo, NY revealed no association between either fat or fiber intake and breast cancer risk (5), but this study suffered from the problems arising from recruitment within a homogeneous population and from the use of a relatively crude dietary questionnaire. An interesting clinical study by Petrakis and King (6) provides some indirect support for the theory that dietary fiber may exert a suppressive influence on breast cancer development. They observed that healthy women with a history of chronic constipation were more likely to have abnormal epithelial cells in breast fluid collected by nipple aspiration than those without such a history. The inference was that both the constipation and the mammary epithelial dysplasia were related to a low consumption of fiber-containing foods. Biological Mechanisms
While nutritional epidemiological investigations can provide clues to the role of dietary factors in cancer etiology, it is essential that these be reinforced by studies designed to determine likely biological mechanisms for the postulated effect on the carcinogenic process. With regard to breast cancer, the focus so far has been on diet-hormone interactions. The involvement of the reproductive hormones in breast cancer development and progression is established. Support for this conclusion includes the adverse effects of early menarche and late menopause on breast cancer risk and the protective effect of an early first completed pregnancy and of bilateral oophorectomy before the age of 40 years. Endocrine therapy aimed at eliminating estrogen activity provides a standard approach not only to treatment of the advanced disease but also to the prevention of second primary tumors and recurrence at distant sites after surgery. Recently, laboratory investigations have shown that a proportion of breast cancer patients have excessively high circulating levels of biologically active estrogen (for example, 7-9). Japanese women typically consume less than half the amounts of fat eaten by women in the western countries; they also have a considerably lower breast cancer risk (3). In comparison with British women, who are at high risk for developing breast cancer, Japanese women have lower levels of biologically available serum estradiol and more of the total amount in an inactive form because of binding to sex hormone-binding globulin (10). Another abnormality of the estrogens that may be associated with enhancement of breast cancer risk is an increased 16a-hydroxylation of estrone, a putative mammary carcinogen (11), the production of which is diminished when women are placed on a low-fat diet (12). Influence on Diet on Estrogen Metabolism In recent years, there has been a gradual accumulation of evidence that supports the hypothesis that dietary fiber, as well as fat, can modify the biological action of hormones and thus influence the risk of sex hormone-related cancers. Endocrine and metabolic studies
2
Nutrition and Cancer 1990
Downloaded by [University of Sussex Library] at 15:12 25 March 2015
of vegetarians and omnivorous women provide a "ready-made" comparison of high- and low-fiber diets. Goldin and co-workers (13,14) have performed several studies of this type, and they have obtained valuable information regarding the effects of dietary fiber and fat on estrogen metabolism and excretion. In one of these (13), the subjects were white American premenopausal female volunteers. Th; vegetarians, on average, consumed 28 g of fiber and 30% of total calories as fat per day; the omnivores daily intake averaged only 12 g of fiber but 40% of total calories as fat. A higher fecal excretion of estrogens by the vegetarians correlated with greater fecal bulk due to the high dietary (and fecal) fiber content. The plasma estrogen levels were negatively correlated with the fecal estrogen excretion in both vegetarians and omnivores, while the vegetarians had a lower urinary excretion of estriol, a metabolite of 16a-hydroxyestrone, the putative carcinogenic steroid referred to in the previous section. A second study by these investigators (14) compared estrogen levels in premenopausal and postmenopausal white Americans witli those of recent immigrants to Hawaii from southeast Asia, who would be at a relatively low breast cancer risk. As anticipated, although the Asian immigrants were not strictly vegetarians there were pronounced differences in the diets of the two groups. In particular, the Oriental women consumed considerably less fat, whereas fiber intake was about 20% lower for the white women. Both the premenopausal and postmenopausal Oriental women had significantly lower plasma estrogen levels than the corresponding groups of Caucasians. Statistical analysis of the associations between estrogen levels and dietary components was performed only for the premenopausal groups. It showed a positive correlation between dietary fat intake and the plasma estrogens. In addition, there was an inverse correlation between dietary fiber intake and plasma estrogen both within and across groups. Fecal estrogen excretion was higher and total urinary estrogen excretion lower in the Oriental women regardless of menopausal status. The mechanisms by which estrogens are influenced by dietary fat and fiber appear to involve their enterohepatic recirculation (Figure 1). Estrogens are conjugated with glucuronic acid and sulfate in the liver and are excreted via the biliary system into the intestinal tract. Here, extensive deconjugation takes place, catalyzed by enzymes of the intestinal microflora. The deconjugated estrogens are then available for reabsorption from the intestine, are transported in the portal system, and contribute to the total estrogen pool that determines the level of both circulating steroids and urinary excretory levels. The importance of bacterial activity in the regulation of this enterohepatic recirculation was established by Adlercreutz and co-workers (15) when they demonstrated the pronounced decreases in urinary estrogen excretion that occur when the intestinal microflora are suppressed by oral ampicillin administration. The hypothesis of breast cancer risk, diet, and the enterohepatic circulation of estrogens has been discussed in-depth in a review article by Gorbach (16). Vegetarians have lower levels of fecal bacterial /3-glucuronidase activity than do nonvegetarians; in the study performed by Goldin and colleagues (13) the enzyme levels were positively correlated with saturated fat intake but were not related to dietary fiber. Fiber within the intestine does, however, influence the activity of deconjugating bacteria. Unpublished studies from our laboratories have shown that increasing the consumption of selected cereal brans, without changing fat intake, produces a reduction in fecal /3glucuronidase activity in premenopausal women. An additional mechanism by which dietary fiber may exert an influence on the enterohepatic recirculation of estrogens has been proposed by Shultz and others (17,18). Their initial study (17) consisted of in vitro experiments that showed that the unconjugated estrogens bind to various types of fiber, of which lignin was the most effective, followed by wheat, oat, and corn brans. The estrogen conjugate estrone-3-glucuronide had considerably less capacity for binding to any of these natural fibers. More recently it was found that
Vol. 13, Nos. 1 & 2
3
Conjugated estrogens Biliary Excretion
Circulating Estrogens
/
V
Hepatic Conjugation of Estrogens
Unconjugated Estrogens
Downloaded by [University of Sussex Library] at 15:12 25 March 2015
Deconjugation by Bacterial Enzymes
Estrogens bound to Fiber
Urinary Estrogens
Fecal Estrogens
omnivores > vegetarians
vegetarians > omnivores
Figure 1. Enterohepatic recirculation of estrogens. Dietary fat promotes intestinal reabsorption of estrogens by its enhancement of deconjugating enzyme activity, whereas intraluminal fiber retards process.
samples of foods consumed by male vegans and lactoovovegetarians contained more water-insoluble fiber than did food composites from diets eaten by omnivores and that this fiber had a high capacity for binding both estradiol and estrone (18). The results suggest that the binding to dietary fiber of estrogens deconjugated in the intestine by bacterial enzymatic activity may limit enterohepatic recirculation of these steroids. They also indicate that the nature as well as the quantity of fiber consumed may be important. The Lignans While studies of the influence of dietary constituents on estrogen metabolism and excretion continue, an alternative hypothesis for a protective effect of fiber on breast cancer risk has evolved through research into the physiological and clinical significance of lignans. The lignans comprise a class of compounds characterized chemically by the possession of a 2,3-dibenzylbutane skeleton as their basic structure. There are close similarities to the structure of the nonsteroidal estrogen diethylstilbestrol, including an identical distance between the C-3 and C-17 hydroxyl groups. This is a requisite for binding to the estrogen receptor. The lignans originally came to the attention of oncologists because many plant lignans have antimitotic activity (19). More recently, two of these substances, enterolactone and its reduction product enterodiol, have been identified. They are formed in the intestine by bacterial action on plant-derived precursors, absorbed from the gut, and excreted in urine in amounts that increase in direct proportion to the dietary fiber intake (20,21). The administration of oxytetracycline produces a prompt decrease in the excretions of these mammalian lignans in human urine (22). The urinary excretion of lignans increases rapidly when rats previously fed a semipurified diet are transferred to a commercial chow diet (23). This observation may have direct relevance to the postulated suppressive effect of dietary fiber on mammary carcinogenesis, because it has been reported that female rats administered the mammary carcinogen
4
Nutrition and Cancer 1990
Downloaded by [University of Sussex Library] at 15:12 25 March 2015
dimethylbenz[a]anthracene and fed a high fiber-containing commercial stock diet develop fewer tumors than animals fed a low-fiber semipurified diet (24). There are several pieces of evidence that tentatively link together lignans, estrogen biological action, and breast cancer. Adlercreutz and co-workers (25) performed a study of urinary lignans and plasma sex hormone-binding globulin (SHBG) and free testosterone levels in Finnish women. Higher levels of plasma SHBG, as well as lower levels of free estradiol, have been associated with reduced breast cancer risk in some studies (8,26), and an elevation in plasma free testosterone as well as unbound estradiol has been reported in breast cancer patients (9). Thus, the finding of a positive correlation between the lignans and SHBG concentrations, and an inverse relationship between urinary enterolactone and plasma free testosterone, becomes of special interest. These same investigators also found that the intake of dietary fiber was positively correlated with the plasma SHBG concentration. From these several sets of data, they postulated that Iignan precursor-containing fiber-rich foods, by providing for enhanced Iignan biosynthesis, stimulate hepatic SHBG synthesis and so modulate downward the circulating levels of bioactive free steroids. An interesting second possibility is that the lignans can act as natural antiestrogens and so provide a regulator of estrogen bioaciivity. Adlercreutz and colleagues (25) quote evidence that although enterolactone has no demonstrable antiestrogenic properties in vitro, it does exhibit some degree of weak estrogenieity. On the other hand, in in vivo experiments Waters and Knowler (27) obtained evidence of antiestrogen activity when they found that enterolactone inhibits estrogen-stimulated RNA synthesis in rat uterus. There is, of course, no inconsistency in the lignans behaving both as weak estrogens and as antiestrogens. The triphenylethylene derivative tamoxifen generally exhibits estrogenic activity in the mouse, but under specially designed experimental conditions it can also behave as an antiestrogen (28). In humans tamoxifen is used for its antiestrogenic properties in breast cancer therapy, but it acts on the hepatic parenchyma to stimulate the synthesis of SHBG and other binding proteins (29). It may be that the lignans, on passing from the intestine to the liver via the portal circulation, exert an estrogenic: effect on liver cells, so stimulating SHBG synthesis (25). There is a limited amount of data relating the lignans enterolactone and enterodiol to breast cancer risk. Adlercreutz and others (21) found the urinary excretion of enterolactone to be lower in postmenopausal breast cancer patients than in normal postmenopausal omnivorous or vegetarian women living in the Boston area of the United States. Enterodiol excretion was lower only when compared with the vegetarian control group. These results are somewhat difficult to interpret because the breast cancer patients did not appear to consume significantly less fiber than the omnivorous controls did, but the number of subjects in each group was small. Furthermore, as has been true of many case-control studies of diet and cancer risk, the patients and the healthy women were drawn from the same homogeneous population. Any differences in fiber intake were likely to be modest and difficult to detect by the crude instruments available for dietary assessment. In a second study (25), which avoided this problem of homogeneity by including healthy premenopausal women in Boston and Finland, particularly low levels of urinary enterolactone excretion were observed in the American omnivores at high risk for breast cancer; the excretions by lactovegetarians and, particularly, those on a macrobiotic diet were much higher (Table 1). Omnivorous women in Helsinki averaged a somewhat higher excretion of the lignans than the American women did, whereas in North Karelia, a rural region of Finland with a lower breast cancer incidence than urban Helsinki, the levels in omnivores approached those of lactovegetarians in Helsinki. The urinary patterns reflect the high dietary fiber intakes of Finnish women regardless of whether they avoid animal food sources. These patterns are consistent with the known patterns of breast cancer incidence in the different geographical regions of Finland and in the metropolitan United States.
Vol. 13, Nos. 1 & 2
5
Table 1. Urinary Excretion of the Lignan Enterolactone in Premenopausal Women With Different Dietary Practices in Various Locations" Diet
Location*
Averge Urinary Enterolactone, nmol/24 hrs
Omnivorous Omnivorous Omnivorous Lactovegetarian Lactovegetarian Macrobiotic
Boston Helsinki N. Karelia Boston Helsinki Boston
2,050 2,460 3,020 4,170 3,650 17,680
a: Prepared from data published by AdlercreutE and co-workers (25). b: All locations are urban except N. Karelia, which is rural.
Downloaded by [University of Sussex Library] at 15:12 25 March 2015
The Lactogenic Hormones Another lead to the mechanisms by which dietary fiber may influence breast cancer risk comes from studies of growth hormone, which acts as a lactogen in humans. Fentiman and co-workers (30) found plasma growth hormone, determined by radioimmunoassay, to be elevated in vegetarian compared with omnivorous women. Subsequently, Rose and others (31) reported that serum growth hormone levels, measured by the same technique, were higher in Finnish than in American women. Even more remarkable were the results of growth hormone radioimmunoassays of breast fluid samples obtained by nipple aspiration. While the hormone was absent from virtually all of the fluids collected from American women, extremely high concentrations were observed in the samples from Finnish women. In contrast, when an immunoradiometric assay that identified only the biologically active 22,000-dalton-molecular-weight growth hormone was used in place of the conventional radioimmunoassay, high levels were no longer detected in Finnish women. It was postulated that either dietary fiber, or associated metabolic derivatives such as the lignans, affect the synthesis or posttranslational production of a growth hormone variant. Such a protein may compete with prolactin for mammary lactogenic hormone receptors, and thus modulate hormonal stimulation of breast tissue, and therefore suppress the promotional phase of carcinogenesis. Future Research Directions
The immediate need is for carefully controlled human experimental dietary studies to evaluate the effects of different fiber sources (e.g., oat, wheat, and corn brans) on circulating levels of hormones and on their bioavailability, metabolism, and excretory patterns. These studies should be performed in combination with specified amounts of dietary fat that reflect the levels consumed in countries of differing breast cancer risk. The exciting work of Adlercreutz and others on the lignans as natural antiestrogens requires confirmation as well as extension to include an evaluation of their protective effect in experimental animal models for mammary carcinogenesis. Additional human studies are needed on the effects of feeding foods rich in lignan precursor-containing fiber on the hepatic synthesis of hormone-binding proteins and consequent bioavailability of sex steroids and on lactogenic hormones and related proteins in various biological fluids. The ultimate test of the relation between dietary fiber (and fat) and breast cancer is the outcome of intervention trials, which would best be done with women at high risk for the disease. A suitable group would be those with biopsied benign breast disease exhibiting atypical hyperplasia. These patients have a breast cancer risk five times that of the general population; this risk increases by 11-fold when a family history of breast cancer is also
6
Nutrition and Cancer 1990
present (32). Because such lesions represent less than 5% of biopsied noncancerous breast disease, a multicenter trial would be mandatory, but the high relative risk should permit attainment of the needed statistical power without the enormous patient entry that would otherwise be necessary. Selection of the: dietary intervention should be based on the outcome of experimental studies referred to earlier. Acknowledgments and Notes Address reprint requests to Dr. D.P. Rose, Div. of Nutrition and Endocrinology, American Health Foundation, 1 Dana Rd., Valhalla, NY 10595. Submitted 23 March 1989; accepted in final form 2 May 1989.
References
Downloaded by [University of Sussex Library] at 15:12 25 March 2015
1. Rose, DP, Boyar, AP, and Wynder, EL: "International Comparisons of Mortality Rates for Cancer of the Breast, Ovary, Prostate, and Colon, and Per Capita Food Consumption." Cancer 58, 2363-2371, 1986. 2. Reddy, BS: "Diet and Colon Cancer: Evidence From Human and Animal Model Studies." In Diet, Nutrition, and Cancer: A Critical Evaluation, BS Reddy and LA Cohen (eds). Boca Raton, FL: CRC, 1986, vol 1, pp 47-65. 3. Rose, DP: "Dietary Factors and Breast Cancer." Cancer Surv 5, 671-687, 1986. 4. Lubin, F, Wax, Y, and Modan, B: "Role of Fat, Animal Protein and Dietary Fiber in Breast Cancer Etiology: A Case Control Study." JNCI 77, 605-612, 1986. 5. Graham, S, Marshall, J, Mettlin, C, Rzepka, T, Nomoto, T, et al.: "Diet in the Etiology of Breast Cancer." Am J Epidemiol 116, 68-75, 1982. 6. Petrakis, NL, and King, EB: "Cytological Abnormalities in Nipple Aspirates of Breast Fluid From Women With Severe Constipation." Lancet 2, 1203, 1981. 7. Moore, JW, Clark, GMG, Bulbrook, RD, Hayward, JL, Murai, JT, et al.: "Serum Concentrations of Total and Non-Protein-Bound Oestradiol in Patients With Breast Cancer and in Normal Controls." Int J Cancer 20, 17-21, 1982. 8. Jones, LA, Ota, DM, Jackson, GA, Jackson, PM, Kemp, K, et al.: "Bioavailability of Estradiol as a Marker for Breast Cancer Risk Assessment." Cancer Res 47, 5224-5229, 1987. 9. Takatani, O, Kosano, H, Okumoto, T, Ahamatsu, K, Tamakuma, S, et al.: "Distribution of Estradiol and Percentage of Free Testosterone in Sera of Japanese Women: Preoperative Breast Cancer Patients and Normal Controls." JNCI 79, 1199-1204, 1987. 10. Moore, JW, Clark, GMG, Takatani, O, Wiikabayashi, Y, Hayward, JL, et al.: "Distribution of 17β-Estradiol in the Sera of Normal British and Japanese Women." JNCI 71, 749-754, 1983. 11. Yu, SC, and Fishman, J: "Interaction of Histones With Estrogens. Covalent Adduct Formation With 16α-Hydroxy-Estrone." Biochemistry 24, 8017-8021, 1985. 12. Longcope, C, Gorbach, S, Goldin, B, Woods, M, Dwyer, J, et al.: "The Effect of a Low Fat Diet on Estrogen Metabolism." J Clin Endocrinol Metab 64, 1246-1250, 1987. 13. Goldin, BR, Adlercreutz, H, Gorbach, SL, Warram, JH, Dwyer, JT, et al.: "Estrogen Excretion Patterns and Plasma Levels in Vegetarian and Omnivorous Women." N Engl J Med 307, 1542-1547, 1982. 14. Goldin, BR, Adlecreutz, H, Gorbach, SL, Woods, MN, Dwyer, JT, et al.: "The Relationship Between Estrogen Levels and Diets of Caucasian American and Oriental Immigrant Women." Am J Clin Nutr 44, 945-953, 1986. 15. Adlercreutz, H, Martin, F, Tikkanen, MJ, and Pulkkinen, M: "Effect of Ampicillin Administration on the Excretion of Twelve Oestrogens in Pregnancy Urine." Acta Endocrinol 80, 551-557, 1975. 16. Gorbach, SL: "Estrogens, Breast Cancer, and Intestinal Flora." Rev Infect Dis 6 Suppl 1, S85-S90, 1984. 17. Shultz, TD, and Howie BJ: "In Vitro Bindng of Steroid Hormones by Natural and Purified Fibers." Nutr Cancer 8, 141-147, 1986. 18. Whitten, CG, and Shultz, TD: "Binding of Steroid Hormone In Vitro by Water-Insoluble Dietary Fiber." FASEB J 1, A862, 1988. 19. Hartwell, JL: "Types of Anticancer Agents Isolated From Plants." Cancer Treat Rep 60, 1031-1067, 1976. 20. Adlercreutz, H, Fotsis, T, Heikkinen, R, Dwyer, JT, Goldin, BR, et al.: "Diet and Urinary Excretion of Lignans in Female Subjects." Med Biol 59, 259-261, 1981. 21. Adlercreutz, H, Fotsis, T, Heikkinen, R, Dwyer, JT, Woods, M, et al.: "Excretion of the Lignans Enterolactone and Enterodiol and of Equol in Omnivorous and Vegetarian Postmenopausal Women and in Women With Breast Cancer." Lancet 2, 1295-1299, 1982. 22. Setchell, KDR, Lawson, AM, Borriello, SP, Harkness, R, Gordon, H, et al.: "Lignan Formation in Man — Microbial Involvement and Possible Role in Cancer." Lancet 2, 4-7, 1981.
Vol. 13, Nos. 1 & 2
7
Downloaded by [University of Sussex Library] at 15:12 25 March 2015
23. Axelson, M, Sjövall, J, Gustafsson, BE, and Setchell, KDR: "Origin of Lignans in Mammals and Identification of a Precursor From Plants." Nature 298, 659-660, 1982. 24. Carroll, KK, and Khor, TT: "Effects of Level and Type of Dietary Fat on Incidence of Mammary Tumors Induced in Female Sprague-Dawley Rats by Dimethylbenz[a]anthracene." Lipids 6, 415-420, 1971. 25. Adlercreutz, H, Fotsis, T, Bannwart, C, Wähälä, I, Mäkelä, T, et al.: "Determination of Urinary Lignans and Phytoestrogen Metabolites, Potential Antiestrogens and Anticarcinogens, in Urine of Women on Various Habitual Diets." J Steroid Biochem 25, 791-797, 1986. 26. Moore, JW, Key, TJA, Bulbrook, RD, Clark, GMG, Allen, DS, et al.: "Sex Hormone Binding Globulin and Risk Factors for Breast Cancer in a Population of Normal Women Who Had Never Used Exogenous Sex Hormones." Br J Cancer 56, 661-666, 1987. 27. Waters, AP, and Knowler, JT: "Effect of a Lignan (HPMF) on RNA Synthesis in the Rat Uterus." J Reprod Fertil 66, 379-381, 1982. 28. Emmens, CW: "Compounds Exhibiting Prolonged Antioestrogenic and Antifertility Activity in Mice and Rats." J Reprod Fertil 26, 175-182, 1971. 29. Sakai, F, Cheix, F, Clavel, M, Colon, J, Mayer, M, et al.: "Increases in Steroid Binding Globulins Induced by Tamoxifen in Patients With Carcinoma of the Breast." J Endocrinol 76, 219-226, 1978. 30. Fentiman, IS, Caleffi, M, Wang, DY, Hampson, SJ, Hoare, SA, et al.: "Diurnal Variations in Prolactin and Growth Hormone Levels in Normal Premenopausal Vegetarian and Omnivorous Women." Nutr Cancer 8, 239-245, 1986. 31. Rose, DP, Boyar, AP, and Kettunen, K: "Diet, Serum, Breast Fluid Growth Hormone, and Prolactin Levels in Normal Premenopausal Finnish and American Women." Nutr Cancer 11, 179-187, 1988. 32. Dupont, WD, and Page, DL: "Risk Factors for Breast Cancer in Women With Proliferative Breast Disease." N Engl J Med 312, 146-151, 1985.
8
Nutrition and Cancer 1990
Nutrition and Cancer Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/hnuc20
Dietary fiber and breast cancer David P. Rose
a
a
Division of Nutrition and Endocrinology , American Health Foundation , 1 Dana Rd., Valhalla, NY, 10595 Published online: 04 Aug 2009.
To cite this article: David P. Rose (1990) Dietary fiber and breast cancer, Nutrition and Cancer, 13:1-2, 1-8, DOI: 10.1080/01635589009514040 To link to this article: http://dx.doi.org/10.1080/01635589009514040
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://www.tandfonline.com/page/ terms-and-conditions
Review
Dietary Fiber and Breast Cancer
Downloaded by [University of Sussex Library] at 15:12 25 March 2015
David P. Rose
Abstract Evidence from epidemiological studies suggests that dietary fiber, as well as fat, has the potential for affecting breast cancer risk. Fiber may have a protective role because of its influence on estrogen metabolism and excretion or because of the endocrine effects of the lignans, a family of compounds formed in the intestine from fiber-associated precursors. Future research should include additional mechanistic studies and dietary intervention trials in groups of women that have a high risk of breast cancer. (Nutr Cancer 13, 1-8, 1990)
Introduction
In general, international comparisons show both a strong positive correlation between the age-adjusted mortality rates for breast and colon cancers and an association between these two tumors and diets that are high in animal fats (1). In addition to wide acceptance for a protective effect of dietary fiber against colon cancer, which is supported by both epidemiological and experimental data (2), recent observations suggest that this proposed benefit of relatively high fiber intakes may also extend to breast cancer. One problem with performing epidemiological studies of diet and cancer risk is that in most human populations a high-fat intake is associated with a low-fiber intake and vice versa. An instructive exception exists in Finland. Here, dietary fat consumption is very high but so also is fiber intake. Moreover, while the United States, for example, has a high breast cancer mortality rate (the age-adjusted figure for 1978-1979 was 22.19/100,000), the risk for Finnish women is considerably less (14.87/100,000). A modifying influence of fiber on the breast cancer risk associated with high-fat intake may explain, at least in part, the lower incidence of this disease in Finland compared with the United States (3). Another difficulty in the case of fiber, to which insufficient consideration has been given in the past, is that the term includes a wide range of plant cell wall and interstitial components with distinct chemical and biological properties. D. P. Rose is affiliated with the Division of Nutrition and Endocrinology, American Health Foundation, Valhalla, NY 10595.
Copyright © 1990, Lawrence Erlbaum Associates, Inc.
Downloaded by [University of Sussex Library] at 15:12 25 March 2015
Epidemiological Studies
Case-control studies of diet and cancer are frequently handicapped by the homogeneity of dietary practices in a given population. Israel is one of several locations that, because of different cultural backgrounds within the same population, do provide a useful range of intakes of key nutrients. Lubin and co-workers (4), using state-of-the-art methodology, examined the relationships between dietary fat and fiber and breast cancer in that country. They found that a high-fat/low-fiber diet was associated with a doubling of breast cancer risk when a relative risk of 1.0 was assigned to those with the lowest fat and high fiber intakes. When the independent effects of the two dietary constituents were evaluated, fat had a strongly positive association with risk; increasing fiber intakes were negatively correlated with risk, although the relationship was not as strong as the positive one for dietary fat. An earlier study from Buffalo, NY revealed no association between either fat or fiber intake and breast cancer risk (5), but this study suffered from the problems arising from recruitment within a homogeneous population and from the use of a relatively crude dietary questionnaire. An interesting clinical study by Petrakis and King (6) provides some indirect support for the theory that dietary fiber may exert a suppressive influence on breast cancer development. They observed that healthy women with a history of chronic constipation were more likely to have abnormal epithelial cells in breast fluid collected by nipple aspiration than those without such a history. The inference was that both the constipation and the mammary epithelial dysplasia were related to a low consumption of fiber-containing foods. Biological Mechanisms
While nutritional epidemiological investigations can provide clues to the role of dietary factors in cancer etiology, it is essential that these be reinforced by studies designed to determine likely biological mechanisms for the postulated effect on the carcinogenic process. With regard to breast cancer, the focus so far has been on diet-hormone interactions. The involvement of the reproductive hormones in breast cancer development and progression is established. Support for this conclusion includes the adverse effects of early menarche and late menopause on breast cancer risk and the protective effect of an early first completed pregnancy and of bilateral oophorectomy before the age of 40 years. Endocrine therapy aimed at eliminating estrogen activity provides a standard approach not only to treatment of the advanced disease but also to the prevention of second primary tumors and recurrence at distant sites after surgery. Recently, laboratory investigations have shown that a proportion of breast cancer patients have excessively high circulating levels of biologically active estrogen (for example, 7-9). Japanese women typically consume less than half the amounts of fat eaten by women in the western countries; they also have a considerably lower breast cancer risk (3). In comparison with British women, who are at high risk for developing breast cancer, Japanese women have lower levels of biologically available serum estradiol and more of the total amount in an inactive form because of binding to sex hormone-binding globulin (10). Another abnormality of the estrogens that may be associated with enhancement of breast cancer risk is an increased 16a-hydroxylation of estrone, a putative mammary carcinogen (11), the production of which is diminished when women are placed on a low-fat diet (12). Influence on Diet on Estrogen Metabolism In recent years, there has been a gradual accumulation of evidence that supports the hypothesis that dietary fiber, as well as fat, can modify the biological action of hormones and thus influence the risk of sex hormone-related cancers. Endocrine and metabolic studies
2
Nutrition and Cancer 1990
Downloaded by [University of Sussex Library] at 15:12 25 March 2015
of vegetarians and omnivorous women provide a "ready-made" comparison of high- and low-fiber diets. Goldin and co-workers (13,14) have performed several studies of this type, and they have obtained valuable information regarding the effects of dietary fiber and fat on estrogen metabolism and excretion. In one of these (13), the subjects were white American premenopausal female volunteers. Th; vegetarians, on average, consumed 28 g of fiber and 30% of total calories as fat per day; the omnivores daily intake averaged only 12 g of fiber but 40% of total calories as fat. A higher fecal excretion of estrogens by the vegetarians correlated with greater fecal bulk due to the high dietary (and fecal) fiber content. The plasma estrogen levels were negatively correlated with the fecal estrogen excretion in both vegetarians and omnivores, while the vegetarians had a lower urinary excretion of estriol, a metabolite of 16a-hydroxyestrone, the putative carcinogenic steroid referred to in the previous section. A second study by these investigators (14) compared estrogen levels in premenopausal and postmenopausal white Americans witli those of recent immigrants to Hawaii from southeast Asia, who would be at a relatively low breast cancer risk. As anticipated, although the Asian immigrants were not strictly vegetarians there were pronounced differences in the diets of the two groups. In particular, the Oriental women consumed considerably less fat, whereas fiber intake was about 20% lower for the white women. Both the premenopausal and postmenopausal Oriental women had significantly lower plasma estrogen levels than the corresponding groups of Caucasians. Statistical analysis of the associations between estrogen levels and dietary components was performed only for the premenopausal groups. It showed a positive correlation between dietary fat intake and the plasma estrogens. In addition, there was an inverse correlation between dietary fiber intake and plasma estrogen both within and across groups. Fecal estrogen excretion was higher and total urinary estrogen excretion lower in the Oriental women regardless of menopausal status. The mechanisms by which estrogens are influenced by dietary fat and fiber appear to involve their enterohepatic recirculation (Figure 1). Estrogens are conjugated with glucuronic acid and sulfate in the liver and are excreted via the biliary system into the intestinal tract. Here, extensive deconjugation takes place, catalyzed by enzymes of the intestinal microflora. The deconjugated estrogens are then available for reabsorption from the intestine, are transported in the portal system, and contribute to the total estrogen pool that determines the level of both circulating steroids and urinary excretory levels. The importance of bacterial activity in the regulation of this enterohepatic recirculation was established by Adlercreutz and co-workers (15) when they demonstrated the pronounced decreases in urinary estrogen excretion that occur when the intestinal microflora are suppressed by oral ampicillin administration. The hypothesis of breast cancer risk, diet, and the enterohepatic circulation of estrogens has been discussed in-depth in a review article by Gorbach (16). Vegetarians have lower levels of fecal bacterial /3-glucuronidase activity than do nonvegetarians; in the study performed by Goldin and colleagues (13) the enzyme levels were positively correlated with saturated fat intake but were not related to dietary fiber. Fiber within the intestine does, however, influence the activity of deconjugating bacteria. Unpublished studies from our laboratories have shown that increasing the consumption of selected cereal brans, without changing fat intake, produces a reduction in fecal /3glucuronidase activity in premenopausal women. An additional mechanism by which dietary fiber may exert an influence on the enterohepatic recirculation of estrogens has been proposed by Shultz and others (17,18). Their initial study (17) consisted of in vitro experiments that showed that the unconjugated estrogens bind to various types of fiber, of which lignin was the most effective, followed by wheat, oat, and corn brans. The estrogen conjugate estrone-3-glucuronide had considerably less capacity for binding to any of these natural fibers. More recently it was found that
Vol. 13, Nos. 1 & 2
3
Conjugated estrogens Biliary Excretion
Circulating Estrogens
/
V
Hepatic Conjugation of Estrogens
Unconjugated Estrogens
Downloaded by [University of Sussex Library] at 15:12 25 March 2015
Deconjugation by Bacterial Enzymes
Estrogens bound to Fiber
Urinary Estrogens
Fecal Estrogens
omnivores > vegetarians
vegetarians > omnivores
Figure 1. Enterohepatic recirculation of estrogens. Dietary fat promotes intestinal reabsorption of estrogens by its enhancement of deconjugating enzyme activity, whereas intraluminal fiber retards process.
samples of foods consumed by male vegans and lactoovovegetarians contained more water-insoluble fiber than did food composites from diets eaten by omnivores and that this fiber had a high capacity for binding both estradiol and estrone (18). The results suggest that the binding to dietary fiber of estrogens deconjugated in the intestine by bacterial enzymatic activity may limit enterohepatic recirculation of these steroids. They also indicate that the nature as well as the quantity of fiber consumed may be important. The Lignans While studies of the influence of dietary constituents on estrogen metabolism and excretion continue, an alternative hypothesis for a protective effect of fiber on breast cancer risk has evolved through research into the physiological and clinical significance of lignans. The lignans comprise a class of compounds characterized chemically by the possession of a 2,3-dibenzylbutane skeleton as their basic structure. There are close similarities to the structure of the nonsteroidal estrogen diethylstilbestrol, including an identical distance between the C-3 and C-17 hydroxyl groups. This is a requisite for binding to the estrogen receptor. The lignans originally came to the attention of oncologists because many plant lignans have antimitotic activity (19). More recently, two of these substances, enterolactone and its reduction product enterodiol, have been identified. They are formed in the intestine by bacterial action on plant-derived precursors, absorbed from the gut, and excreted in urine in amounts that increase in direct proportion to the dietary fiber intake (20,21). The administration of oxytetracycline produces a prompt decrease in the excretions of these mammalian lignans in human urine (22). The urinary excretion of lignans increases rapidly when rats previously fed a semipurified diet are transferred to a commercial chow diet (23). This observation may have direct relevance to the postulated suppressive effect of dietary fiber on mammary carcinogenesis, because it has been reported that female rats administered the mammary carcinogen
4
Nutrition and Cancer 1990
Downloaded by [University of Sussex Library] at 15:12 25 March 2015
dimethylbenz[a]anthracene and fed a high fiber-containing commercial stock diet develop fewer tumors than animals fed a low-fiber semipurified diet (24). There are several pieces of evidence that tentatively link together lignans, estrogen biological action, and breast cancer. Adlercreutz and co-workers (25) performed a study of urinary lignans and plasma sex hormone-binding globulin (SHBG) and free testosterone levels in Finnish women. Higher levels of plasma SHBG, as well as lower levels of free estradiol, have been associated with reduced breast cancer risk in some studies (8,26), and an elevation in plasma free testosterone as well as unbound estradiol has been reported in breast cancer patients (9). Thus, the finding of a positive correlation between the lignans and SHBG concentrations, and an inverse relationship between urinary enterolactone and plasma free testosterone, becomes of special interest. These same investigators also found that the intake of dietary fiber was positively correlated with the plasma SHBG concentration. From these several sets of data, they postulated that Iignan precursor-containing fiber-rich foods, by providing for enhanced Iignan biosynthesis, stimulate hepatic SHBG synthesis and so modulate downward the circulating levels of bioactive free steroids. An interesting second possibility is that the lignans can act as natural antiestrogens and so provide a regulator of estrogen bioaciivity. Adlercreutz and colleagues (25) quote evidence that although enterolactone has no demonstrable antiestrogenic properties in vitro, it does exhibit some degree of weak estrogenieity. On the other hand, in in vivo experiments Waters and Knowler (27) obtained evidence of antiestrogen activity when they found that enterolactone inhibits estrogen-stimulated RNA synthesis in rat uterus. There is, of course, no inconsistency in the lignans behaving both as weak estrogens and as antiestrogens. The triphenylethylene derivative tamoxifen generally exhibits estrogenic activity in the mouse, but under specially designed experimental conditions it can also behave as an antiestrogen (28). In humans tamoxifen is used for its antiestrogenic properties in breast cancer therapy, but it acts on the hepatic parenchyma to stimulate the synthesis of SHBG and other binding proteins (29). It may be that the lignans, on passing from the intestine to the liver via the portal circulation, exert an estrogenic: effect on liver cells, so stimulating SHBG synthesis (25). There is a limited amount of data relating the lignans enterolactone and enterodiol to breast cancer risk. Adlercreutz and others (21) found the urinary excretion of enterolactone to be lower in postmenopausal breast cancer patients than in normal postmenopausal omnivorous or vegetarian women living in the Boston area of the United States. Enterodiol excretion was lower only when compared with the vegetarian control group. These results are somewhat difficult to interpret because the breast cancer patients did not appear to consume significantly less fiber than the omnivorous controls did, but the number of subjects in each group was small. Furthermore, as has been true of many case-control studies of diet and cancer risk, the patients and the healthy women were drawn from the same homogeneous population. Any differences in fiber intake were likely to be modest and difficult to detect by the crude instruments available for dietary assessment. In a second study (25), which avoided this problem of homogeneity by including healthy premenopausal women in Boston and Finland, particularly low levels of urinary enterolactone excretion were observed in the American omnivores at high risk for breast cancer; the excretions by lactovegetarians and, particularly, those on a macrobiotic diet were much higher (Table 1). Omnivorous women in Helsinki averaged a somewhat higher excretion of the lignans than the American women did, whereas in North Karelia, a rural region of Finland with a lower breast cancer incidence than urban Helsinki, the levels in omnivores approached those of lactovegetarians in Helsinki. The urinary patterns reflect the high dietary fiber intakes of Finnish women regardless of whether they avoid animal food sources. These patterns are consistent with the known patterns of breast cancer incidence in the different geographical regions of Finland and in the metropolitan United States.
Vol. 13, Nos. 1 & 2
5
Table 1. Urinary Excretion of the Lignan Enterolactone in Premenopausal Women With Different Dietary Practices in Various Locations" Diet
Location*
Averge Urinary Enterolactone, nmol/24 hrs
Omnivorous Omnivorous Omnivorous Lactovegetarian Lactovegetarian Macrobiotic
Boston Helsinki N. Karelia Boston Helsinki Boston
2,050 2,460 3,020 4,170 3,650 17,680
a: Prepared from data published by AdlercreutE and co-workers (25). b: All locations are urban except N. Karelia, which is rural.
Downloaded by [University of Sussex Library] at 15:12 25 March 2015
The Lactogenic Hormones Another lead to the mechanisms by which dietary fiber may influence breast cancer risk comes from studies of growth hormone, which acts as a lactogen in humans. Fentiman and co-workers (30) found plasma growth hormone, determined by radioimmunoassay, to be elevated in vegetarian compared with omnivorous women. Subsequently, Rose and others (31) reported that serum growth hormone levels, measured by the same technique, were higher in Finnish than in American women. Even more remarkable were the results of growth hormone radioimmunoassays of breast fluid samples obtained by nipple aspiration. While the hormone was absent from virtually all of the fluids collected from American women, extremely high concentrations were observed in the samples from Finnish women. In contrast, when an immunoradiometric assay that identified only the biologically active 22,000-dalton-molecular-weight growth hormone was used in place of the conventional radioimmunoassay, high levels were no longer detected in Finnish women. It was postulated that either dietary fiber, or associated metabolic derivatives such as the lignans, affect the synthesis or posttranslational production of a growth hormone variant. Such a protein may compete with prolactin for mammary lactogenic hormone receptors, and thus modulate hormonal stimulation of breast tissue, and therefore suppress the promotional phase of carcinogenesis. Future Research Directions
The immediate need is for carefully controlled human experimental dietary studies to evaluate the effects of different fiber sources (e.g., oat, wheat, and corn brans) on circulating levels of hormones and on their bioavailability, metabolism, and excretory patterns. These studies should be performed in combination with specified amounts of dietary fat that reflect the levels consumed in countries of differing breast cancer risk. The exciting work of Adlercreutz and others on the lignans as natural antiestrogens requires confirmation as well as extension to include an evaluation of their protective effect in experimental animal models for mammary carcinogenesis. Additional human studies are needed on the effects of feeding foods rich in lignan precursor-containing fiber on the hepatic synthesis of hormone-binding proteins and consequent bioavailability of sex steroids and on lactogenic hormones and related proteins in various biological fluids. The ultimate test of the relation between dietary fiber (and fat) and breast cancer is the outcome of intervention trials, which would best be done with women at high risk for the disease. A suitable group would be those with biopsied benign breast disease exhibiting atypical hyperplasia. These patients have a breast cancer risk five times that of the general population; this risk increases by 11-fold when a family history of breast cancer is also
6
Nutrition and Cancer 1990
present (32). Because such lesions represent less than 5% of biopsied noncancerous breast disease, a multicenter trial would be mandatory, but the high relative risk should permit attainment of the needed statistical power without the enormous patient entry that would otherwise be necessary. Selection of the: dietary intervention should be based on the outcome of experimental studies referred to earlier. Acknowledgments and Notes Address reprint requests to Dr. D.P. Rose, Div. of Nutrition and Endocrinology, American Health Foundation, 1 Dana Rd., Valhalla, NY 10595. Submitted 23 March 1989; accepted in final form 2 May 1989.
References
Downloaded by [University of Sussex Library] at 15:12 25 March 2015
1. Rose, DP, Boyar, AP, and Wynder, EL: "International Comparisons of Mortality Rates for Cancer of the Breast, Ovary, Prostate, and Colon, and Per Capita Food Consumption." Cancer 58, 2363-2371, 1986. 2. Reddy, BS: "Diet and Colon Cancer: Evidence From Human and Animal Model Studies." In Diet, Nutrition, and Cancer: A Critical Evaluation, BS Reddy and LA Cohen (eds). Boca Raton, FL: CRC, 1986, vol 1, pp 47-65. 3. Rose, DP: "Dietary Factors and Breast Cancer." Cancer Surv 5, 671-687, 1986. 4. Lubin, F, Wax, Y, and Modan, B: "Role of Fat, Animal Protein and Dietary Fiber in Breast Cancer Etiology: A Case Control Study." JNCI 77, 605-612, 1986. 5. Graham, S, Marshall, J, Mettlin, C, Rzepka, T, Nomoto, T, et al.: "Diet in the Etiology of Breast Cancer." Am J Epidemiol 116, 68-75, 1982. 6. Petrakis, NL, and King, EB: "Cytological Abnormalities in Nipple Aspirates of Breast Fluid From Women With Severe Constipation." Lancet 2, 1203, 1981. 7. Moore, JW, Clark, GMG, Bulbrook, RD, Hayward, JL, Murai, JT, et al.: "Serum Concentrations of Total and Non-Protein-Bound Oestradiol in Patients With Breast Cancer and in Normal Controls." Int J Cancer 20, 17-21, 1982. 8. Jones, LA, Ota, DM, Jackson, GA, Jackson, PM, Kemp, K, et al.: "Bioavailability of Estradiol as a Marker for Breast Cancer Risk Assessment." Cancer Res 47, 5224-5229, 1987. 9. Takatani, O, Kosano, H, Okumoto, T, Ahamatsu, K, Tamakuma, S, et al.: "Distribution of Estradiol and Percentage of Free Testosterone in Sera of Japanese Women: Preoperative Breast Cancer Patients and Normal Controls." JNCI 79, 1199-1204, 1987. 10. Moore, JW, Clark, GMG, Takatani, O, Wiikabayashi, Y, Hayward, JL, et al.: "Distribution of 17β-Estradiol in the Sera of Normal British and Japanese Women." JNCI 71, 749-754, 1983. 11. Yu, SC, and Fishman, J: "Interaction of Histones With Estrogens. Covalent Adduct Formation With 16α-Hydroxy-Estrone." Biochemistry 24, 8017-8021, 1985. 12. Longcope, C, Gorbach, S, Goldin, B, Woods, M, Dwyer, J, et al.: "The Effect of a Low Fat Diet on Estrogen Metabolism." J Clin Endocrinol Metab 64, 1246-1250, 1987. 13. Goldin, BR, Adlercreutz, H, Gorbach, SL, Warram, JH, Dwyer, JT, et al.: "Estrogen Excretion Patterns and Plasma Levels in Vegetarian and Omnivorous Women." N Engl J Med 307, 1542-1547, 1982. 14. Goldin, BR, Adlecreutz, H, Gorbach, SL, Woods, MN, Dwyer, JT, et al.: "The Relationship Between Estrogen Levels and Diets of Caucasian American and Oriental Immigrant Women." Am J Clin Nutr 44, 945-953, 1986. 15. Adlercreutz, H, Martin, F, Tikkanen, MJ, and Pulkkinen, M: "Effect of Ampicillin Administration on the Excretion of Twelve Oestrogens in Pregnancy Urine." Acta Endocrinol 80, 551-557, 1975. 16. Gorbach, SL: "Estrogens, Breast Cancer, and Intestinal Flora." Rev Infect Dis 6 Suppl 1, S85-S90, 1984. 17. Shultz, TD, and Howie BJ: "In Vitro Bindng of Steroid Hormones by Natural and Purified Fibers." Nutr Cancer 8, 141-147, 1986. 18. Whitten, CG, and Shultz, TD: "Binding of Steroid Hormone In Vitro by Water-Insoluble Dietary Fiber." FASEB J 1, A862, 1988. 19. Hartwell, JL: "Types of Anticancer Agents Isolated From Plants." Cancer Treat Rep 60, 1031-1067, 1976. 20. Adlercreutz, H, Fotsis, T, Heikkinen, R, Dwyer, JT, Goldin, BR, et al.: "Diet and Urinary Excretion of Lignans in Female Subjects." Med Biol 59, 259-261, 1981. 21. Adlercreutz, H, Fotsis, T, Heikkinen, R, Dwyer, JT, Woods, M, et al.: "Excretion of the Lignans Enterolactone and Enterodiol and of Equol in Omnivorous and Vegetarian Postmenopausal Women and in Women With Breast Cancer." Lancet 2, 1295-1299, 1982. 22. Setchell, KDR, Lawson, AM, Borriello, SP, Harkness, R, Gordon, H, et al.: "Lignan Formation in Man — Microbial Involvement and Possible Role in Cancer." Lancet 2, 4-7, 1981.
Vol. 13, Nos. 1 & 2
7
Downloaded by [University of Sussex Library] at 15:12 25 March 2015
23. Axelson, M, Sjövall, J, Gustafsson, BE, and Setchell, KDR: "Origin of Lignans in Mammals and Identification of a Precursor From Plants." Nature 298, 659-660, 1982. 24. Carroll, KK, and Khor, TT: "Effects of Level and Type of Dietary Fat on Incidence of Mammary Tumors Induced in Female Sprague-Dawley Rats by Dimethylbenz[a]anthracene." Lipids 6, 415-420, 1971. 25. Adlercreutz, H, Fotsis, T, Bannwart, C, Wähälä, I, Mäkelä, T, et al.: "Determination of Urinary Lignans and Phytoestrogen Metabolites, Potential Antiestrogens and Anticarcinogens, in Urine of Women on Various Habitual Diets." J Steroid Biochem 25, 791-797, 1986. 26. Moore, JW, Key, TJA, Bulbrook, RD, Clark, GMG, Allen, DS, et al.: "Sex Hormone Binding Globulin and Risk Factors for Breast Cancer in a Population of Normal Women Who Had Never Used Exogenous Sex Hormones." Br J Cancer 56, 661-666, 1987. 27. Waters, AP, and Knowler, JT: "Effect of a Lignan (HPMF) on RNA Synthesis in the Rat Uterus." J Reprod Fertil 66, 379-381, 1982. 28. Emmens, CW: "Compounds Exhibiting Prolonged Antioestrogenic and Antifertility Activity in Mice and Rats." J Reprod Fertil 26, 175-182, 1971. 29. Sakai, F, Cheix, F, Clavel, M, Colon, J, Mayer, M, et al.: "Increases in Steroid Binding Globulins Induced by Tamoxifen in Patients With Carcinoma of the Breast." J Endocrinol 76, 219-226, 1978. 30. Fentiman, IS, Caleffi, M, Wang, DY, Hampson, SJ, Hoare, SA, et al.: "Diurnal Variations in Prolactin and Growth Hormone Levels in Normal Premenopausal Vegetarian and Omnivorous Women." Nutr Cancer 8, 239-245, 1986. 31. Rose, DP, Boyar, AP, and Kettunen, K: "Diet, Serum, Breast Fluid Growth Hormone, and Prolactin Levels in Normal Premenopausal Finnish and American Women." Nutr Cancer 11, 179-187, 1988. 32. Dupont, WD, and Page, DL: "Risk Factors for Breast Cancer in Women With Proliferative Breast Disease." N Engl J Med 312, 146-151, 1985.
8
Nutrition and Cancer 1990
