Summary
Prepubertal exposure to a pharmacological dose (500 mg kg–1) of the phyto-oestrogen genistein can reduce the incidence and multiplicity of carcinogen-induced mammary tumours in rats. However, such an exposure also disrupts the function of the hypothalamic–pituitary–gonadal axis, making it unsuitable for breast cancer prevention. We studied whether prepubertal exposure to genistein at a total body dose broadly comparable to the level typical of Oriental countries, approximately 1 mg kg–1 body weight, affects mammary tumorigenesis. We also studied whether prepubertal exposure to zearalenone, a major source for phyto-oestrogens in the USA, influences breast cancer risk. Prepubertal rats were treated between postnatal days 7 and 20, with 20 μg (~ 1 mg kg–1 body weight) of either genistein or zearalenone. Zearalenone exposure significantly reduced both the incidence and multiplicity of mammary tumours induced by 7,12-dimethylbenz(a)anthracene (DMBA). Genistein exposure significantly reduced tumour multiplicity, but not tumour incidence, when compared with vehicle-treated animals. Furthermore, 60% of the tumours in the genistein group were not malignant, while all the tumours analysed for histopathology in the vehicle and zearalenone groups were adenocarcinomas. A higher number of differentiated alveolar buds, and lower number of terminal ducts, were present in the DMBA-treated mammary glands of the phyto-oestrogen exposed rats. The concentration of oestrogen receptor (ER) binding sites after the DMBA treatment was low in the mammary glands of all groups but a significantly higher proportion of the glands in the zearalenone exposed rats were ER-positive (i.e. ER levels ≥ 5 fmol mg–1 protein) than the glands of the vehicle controls. Our data suggest that a prepubertal exposure to a low dose of either zearalenone or genistein may protect the mammary gland from carcinogen-induced malignant transformation, possibly by increasing differentiation of the mammary epithelial tree.
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References
Akiyama, T., Ishida, J., Nakagawa, S., Ogawa, H., Watanabe, S., Itou, N., Shibata, M. & Fukami, Y. (1987). Genistein, a specific inhibitor of tyrosine-specific protein kinase. J Biol Chem 262: 5592–5595.
Barnes, S. (1997). The chemopreventive properties of soy isoflavonoids in animal models of breast cancer. Breast Cancer Res Treat 46: 169–179.
Bern, H. A., Mills, K. T. & Edery, M. (1985). Estrogen-associated defects in rodent mammary gland development. In Estrogens in the Environment, McLachlan JA (ed), pp. 319–326 Elsevier: Amsterdam
Burgess, L. W., Nelson, P. E. & Toussoun, T. A. (1982). Characterization, geographic distribution and ecology of Fusarium crookwellense sp. nov. Trans Br Mycol Soc 79: 497–505.
Clark, G. M. & McGuire, W. L. (1988). Steroid receptors and other prognostic factors in primary breast cancer. Semin Oncol 15: 20–25.
Clarke, R. (1997). Issues in experimental design and analysis in the study of experimental cytotoxic agents in vivo in breast cancer and other models. Breast Cancer Res Treat 46: 255–278.
Clarke, R., Dickson, R. B. & Lippman, M. E. (1992). Hormonal aspects of breast cancer. Growth factors, drugs and stromal interactions. Crit Rev Oncol Hematol 12: 1–23.
Collins, B. M., McLachlan, J. A. & Arnold, S. F. (1997). The estrogenic and antiestrogeneic activities of phytochemicals with the human estrogen receptor expressed in yeast. Steroids 62: 365–372.
Ekbom, A., Trichopoulos, D., Adami, H. O., Hsieh, C. C. & Lan, S. J. (1992). Evidence of prenatal influences on breast cancer risk. Lancet 340: 1015–1018.
Faber, K. A. & Hughes, C. L. J. (1991). The effect of neonatal exposure to diethylstilbestrol, genistein, and zearalenone on pituitary responsiveness and sexually dimorphic nucleus volume in the castrated adult rat. Biol Reprod 45: 649–653.
Freireich, E. J., Gehan, E. A., Rall, D. P., Schmidt, L. H. & Skipper, H. E. (1966). Quantitative comparison of toxicity of anticancer agents in the mouse, rat, hamster, dog, monkey and man. Cancer Chemother Rep 50: 219–244.
Fukutake, M., Takahashi, M., Ishida, K., Kawamura, H., Sugimura, T. & Wakabayashi, K. (1996). Quantification of genistein and genistin in soybeans and soybean products. Food Chem Toxicol 34: 457–461.
Gotoh, T., Yamada, K., Yin, H., Ito, A., Kataoka, T. & Dohi, K. (1998). Chemoprevention of N-nitroso-N-methylurea-induced rat mammary carcinogenesis by soy foods or biochanin A. Jpn J Cancer Res 89: 137–142.
Grodstein, F., Stampfer, M. J., Colditz, G. A., Willett, W. C., Manson, J. E., Joffe, M., Rosner, B., Fuchs, C., Hankinson, S. E., Hunter, D. J., Hennekens, C. H. & Speizer, F. E. (1997). Postmenopausal hormone therapy and mortality. N Eng J Med 336: 1769–1775.
Grubbs, C. J., Farneli, D. R., Hill, D. L. & McDonough, K. C. (1985). Chemoprevention of n-nitro-n-methylurea-induced mammary cancers by pretreatment with 17beta-estradiol and progesterone. J Natl Cancer Inst 74: 927–931.
Hagler, W. M., Tyczkowska, K. & Hamilton, P. B. (1984). Simultaneous occurrence of deoxynivalenol, zearalenone, and aflatoxin in 1982 scabby wheat from the Midwestern United States. Appl Environ Microbiol 47: 151–154.
Hanfelt, J. J. (1997). Statistical approaches to experimental design and data analysis of in vivo studies. Breast Cancer Res Treat 46: 279–302.
Harding, C., Tetlow, L., McMichael Phillips, D., Osundeko, O., Potten, C. S. & Bundred, N. J. (1997). Oestrogenic effects of soy on nipple aspirate fluid. Breast Cancer Res Treat 46: 80-Abstract
Haslam, S. Z. (1988). Progesterone effects on deoxyribonucleic acid synthesis in normal mouse mammary glands. Endocrinology 122: 464–470.
Haslam, S. (1989). The ontogeny of mouse mammary gland responsiveness to ovarian steroid hormones. Endocrinology 125: 2766–2772.
Hawrylewicz, E. J., Huang, H. H. & Blair, W. H. (1991). Dietary soybean isolate and methionine supplementation affect mammary tumor progression in rats. J Nutr 121: 1693–1698.
Hilakivi-Clarke, L., Cho, E., Raygada, M. & Kenney, N. (1997a). Alterations in mammary gland development following neonatal exposure to estradiol, transforming growth factor alpha, and estrogen receptor antagonist ICI 182, 780. J Cell Physiol 170: 279–289.
Hilakivi-Clarke, L., Clarke, R., Onojafe, I., Raygada, M., Cho, E. & Lippman, M. E. (1997b). A maternal diet high in n-6 polyunsaturated fats alters mammary gland development, puberty onset, and breast cancer risk among female rat offspring. Proc Natl Acad Sci USA 94: 9372–9377.
Hilakivi-Clarke, L. A., Raygada, M., Stoica, A. & Martin, M-B (1998). Consumption of a high-fat diet during pregnancy alters estrogen receptor content, protein kinase C activity and morphology of mammary gland in the mother and her female offspring. Cancer Res 58: 654–660.
Hirohata, T., Shigematsu, T., Nomura, A. M. Y., Nomura, Y., Horie, A. & Hirohata, I. (1985). Occurrence of breast cancer in relation to diet and reproductive history: a case-control study in Fukuoka, Japan. Natl Cancer Inst Monogr 69: 187–190.
Hsieh, C. Y., Santell, R. C., Haslam, S. Z. & Helferich, W. G. (1998). Estrogenic effects of genistein on the growth of estrogen receptor-positive human breast cancer (MCF-7) cells in vitro and in vivo. Cancer Res 58: 3833–3838.
Ingram, D., Sanders, K., Kolybaba, M. & Lopez, D. (1997). Case-control study of phytoestrogens and breast cancer. Lancet 350: 990–994.
Kuiper-Goodman, T. (1990). Uncertainties in the risk assessment of three mycotoxins: aflatoxin, ochratoxin, and zearalenone. Can J Physiol Pharm 68: 1017–1024.
Lee, H. P., Gourley, L., Duffy, S. W., Esteve, J., Lee, J. & Day, N. E. (1991). Dietary effects on breast cancer risk in Singapore. Lancet 337: 1197–1200.
Lopez, J., Ogren, L., Verjan, R. & Talamantes, F. (1988). Effects of perinatal exposure to a synthetic estrogen and progestin on mammary tumorigenesis in mice. Teratology 38: 129–134.
Lu, L. J., Broemeling, L., Marshall, M. & Ramanujam, V. M. (1995). A simplified method to quantify isoflavones in commercial soybean diets and human urine after legume consumption. Cancer Epidemiol Biomarkers Prev 4: 497–503.
Luo, Y., Yoshizawa, T. & Katayama, T. (1990). Comparative study on the natural occurrence of fusarium mycotoxins (trichothecenes and zearalenone) in corn and wheat from high- and low-risk areas for human esophageal cancer in China. Appl Environ Microbiol 56: 3723–3726.
McMichael-Phillips, D. F., Harding, C., Morton, M., Roberts, S. A., Howell, A., Potten, C. S. & Bundred, N. J. (1998). Effect of soy-protein supplementation on epithelial proliferation in the histologically normal human breast. Am J Clin Nutr 68: (suppl), 1431S–1436S.
Martin, P. M., Horwitz, K. B., Ryan, D. S. & McGuire, W. (1978). Phytoestrogen interaction with estrogen receptors in human breast cancer cells. Endocrinology 103: 1860–1867.
Messina, M., Persky, V., Setchell, K. D. R. & Barnes, S. (1994). Soy intake and breast cancer: a review of the in vitro and in vivo data. Nutr Cancer 21: 113–131.
Michels, K. B., Trichopoulos, D., Robins, J. M., Rosner, B. A., Manson, J. E., Hunter, D., Colditz, G. A., Hankinson, S. E., Speizer, F. E. & Willett, W. C. (1996). Birth weight as a risk factor for breast cancer. Lancet 348: 1542–1546.
Murrill, W. B., Brown, N. M., Zhang, J. X., Manzolillo, P. A., Barnes, S. & Lamartiniere, C. A. (1996). Prepubertal genistein exposure suppresses mammary cancer and enhances gland differentiation in rats. Carcinogenesis 17: 1451–1457.
Nagasawa, H., Yanai, R., Shonodo, M., Nakamura, T. & Tanabe, Y. (1974). Effect of neonatally administered estrogen and prolactin on normal and neoplastic mammary growth and serum estradiol-17 level in rats. Cancer Res 34: 2643–2646.
Nelson, J., Clarke, R., Dickson, G. R., Van Den Berg, H. W. & Murphy, R. F. (1986). The effects of Mg2+ ions or EDTA on nuclear integrity and apparent subcellular distribution of unoccupied oestrogen receptors in breast cancer cells. J Steroid Biochem 25: 619–626.
Nomura, A., Henderson, B. E. & Lee, J. (1978). Breast cancer and diet among the Japanese in Hawaii. Am J Clin Nutr 31: 2020–2025.
Petrakis, N. L., Barnes, S., King, E. B., Lowenstein, J., Wiencke, J., Lee, M. M., Miike, R., Kirk, M. & Coward, L. (1996). Stimulatory influence of soy protein isolate on breast secretion in pre- and postmenopausal women. Cancer Epidemiol Biomark Prev 5: 785–794.
Ralston, A. T. (1978). Effect of zearalanol on weaning weight of male calves. J Anim Sci 47: 1203–1206.
Russo, I. H., Medado, J. & Russo, J. (1994). Endocrine influences on the mammary gland. In Integument and Mammary Glands. Eds TC Jones, U Mohr & RD Hunt. Berlin: Springer-Verlag. pp. 252–266.
Russo, J. & Russo, I. H. (1987). Biological and molecular bases of mammary carcinogenesis. Lab Invest 57: 112–137.
Sanderson, M., Williams, M., Malone, K. E., Stanford, J. L., Emanuel, I., White, E. & Daling, J. R. (1996). Perinatal factors and risk of breast cancer. Epidemiology 7: 34–37.
Santell, R. C., Chang, Y. C., Nair, M. G. & Helferich, W. G. (1997). Dietary genistein exerts estrogeneic effects upon the uterus, mammary gland and the hypothalamic/pituitary axis in rats. J Nutr 127: 263–269.
Schoental, R. (1974). Role of podophyllotoxin in the bedding and dietary zearalenone on incidence of ‘spontaneous’ tumors in laboratory animals. Cancer Res 34: 2419
Schoental, R. (1985). Trichothecenes, Zearalenone, and other carcinogenic metabolites of fusarium and related microfungi. Adv Cancer Res 45: 217–290.
Seow, A., Shi, C-Y, Franke, A., Hankin, J. H., Lee, H. P. & Yu, M. C. (1998). Isoflavoid levels in spot urine are associated with frequency of dietary soy intake in a population-based sample of middle-aged and older Chinese in Singapore. Cancer Epidemiol Biomarkers Prev 7: 135–140.
Setchell, K. D. R., Borriello, S. P., Hulme, P., Kirk, D. N. & Axelson, M. (1984). Nonsteroidal estrogens of dietary origin: possible roles in hormone-dependent disease. Am J Clin Nutr 40: 569–578.
Snedecor, G. W. (1988). Statistical Methods, 8th Edn. Iowa State University Press: Ames, Iowa
Thordarson, G., Jin, E., Guzman, R. C., Swanson, S. M., Nandi, S. & Talamantes, F. (1995). Refractoriness to mammary tumorigenesis in parous rats: is it caused by persistent changes in the hormonal environment or permanent biochemical alterations in the mammary epithelia? Carcinogenesis 16: 2847–2853.
Verhoeven, G., Vandoren, G., Heyns, W., Kuhn, E. R., Janssens, J. P., Teuwen, D., Goddeeris, E., Lesaffre, E. & DeMoor, P. (1982). Incidence, growth and estradiol-receptor levels of 7,12-dimethylbenz(alpha)antracene-induced mammary tumours in rats: effects of neonatal sex steroids and oestradiol implants. J Endocrinol 95: 357–368.
Wang, T. T., Sathyamoorthy, N. & Phang, J. M. (1996). Molecular effects of genistein on estrogen receptor mediated pathways. Carcinogenesis 17: 271–275.
Wiggins, J. P., Rothenbacher, H., Wilson, L. L., Martin, R. J., Wangness, P. J. & Ziegler, J. H. (1979). Growth and endocrine responses of lambs to zearanol implants: effects of preimplant growth rate and breed of sire. J Anim Sci 49: 291–297.
Winstanley, J., Cooke, T., George, W. D., Murray, G., Holt, S., Croton, R., Griffiths, K. & Nicholson, R. (1991). The long term prognostic significance of oestrogen receptor analysis in early carcinoma of the breast. Br J Cancer 64: 99–101.
Witte, J. S., Ursin, G., Siemiatycki, J., Thompson, W. D., Paganini-Hill, A. & Haile, R. W. (1997). Diet and premenopausal bilateral breast cancer: A case-control study. Breast Cancer Res Treat 42: 243–251.
Wu, A. H., Ziegler, R. G., Horn-Ross, P. L., Nomura, A. M. Y., West, D. W., Kolonel, L. N., Rosenthal, J. F., Hoover, R. N. & Pike, M. C. (1996). Tofu and risk of breast cancer in Asian-Americans. Cancer Epidemiol Biomarkers Prev 5: 901–906.
Wu, A. H., Ziegler, R. G., Nomura, A. M. Y., West, D. W., Kolonel, L. N., Horn-Ross, P. L., Hoover, R. N. & Pike, M. C. (1998). Soy intake and risk of breast cancer in Asians and Asian-Americans. Am J Clin Nutr 68: (Suppl), 1437S–1443S.
Yuan, J. M., Wang, Q. S., Ross, R. K., Henderson, B. E. & Yu, M. C. (1995). Diet and breast cancer in Shanghai and Tianjin, China. Br J Cancer 71: 1353–1358.
Zava, D. T. & Duwe, G. (1997). Estrogenic and antiproliferative properties of genistein and other flavonoids in human breast cancer cells in vitro. Nutr Cancer 27: 31–40.
Zheng, W., Dai, Q., Cluster, L. J., Shu, X. O., Wen, W. Q., Jin, F. & Franke, A. A. (1999). Urinary excretion of isoflavonoids and the risk of breast cancer. Cancer Epidemiol Biomarkers Prev 8: 35–40
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This work was supported by grants from the American Cancer Society (CN-80420), and the Lombardi Cancer Center Shared Animal Resource Facility, U.S. Public Health Service Grant 2P30-CA51008.
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Hilakivi-Clarke, L., Onojafe, I., Raygada, M. et al. Prepubertal exposure to zearalenone or genistein reduces mammary tumorigenesis. Br J Cancer 80, 1682–1688 (1999). https://doi.org/10.1038/sj.bjc.6690584
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DOI: https://doi.org/10.1038/sj.bjc.6690584
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