Abstract
We examined the effects of a Japanese fermented soybean product, miso, and tamoxifen (TAM), alone and in combination, on N‐nitroso‐N‐methylurea (MNU)‐induced rat mammary cancer. Seven‐week‐old female CD/Crj rats received a single i.v. dose (50 mg/kg body weight) of MNU. After administration of MNU, the rats were divided into 4 groups: regular diet (control), 10% miso diet, regular diet+TAM, and 10% miso diet+TAM. TAM was implanted s.c. in the form of pellets containing 2.5 mg at the same time as MNU was administered. All rats were observed for 18 weeks after MNU administration. Incidence (percentage of rats with tumors) and multiplicity (mean tumors/rat) of mammary tumors were 91% and 4.5 in the control, 77% and 2.4 (P<0.05) in the 10% miso group, 68% and 1.4 (P<0.01) in the TAM group, and 10% (P<0.0001 or less) and 0.2 (P<0.0001) in the 10% miso+TAM group. In the second experiment, the effect of the combination of miso and TAM on established rat mammary tumors was investigated. When the mammary tumors induced by MNU reached 10 to 25 mm, the rats were divided into 3 treatment groups: regular diet, regular diet+TAM, and 10% miso diet+TAM. At 6 weeks after the start of treatment, the mean tumor size in the control and TAM groups was 160% and 141% of the pretreatment value, but a decrease to 85% of the pretreatment value was produced by the combination of miso and TAM, and this was significantly different from both the control and TAM groups (P<0.01 and P<0.05, respectively). These results indicate that miso is useful in protecting against mammary cancer and it can be expected to have a potent antitumor effect, especially when used in combination with TAM.
Keywords: Key words, Chemoprevention, Rat, Mammary cancer, Miso, Tamoxifen
Full Text
The Full Text of this article is available as a PDF (600.5 KB).
REFERENCES
- 1. ) Tominaga , T. and Kuroishi , T.Epidemiology of breast cancer in Japan . Breast Cancer , 2 , 1 – 7 ( 1995. ). [DOI] [PubMed] [Google Scholar]
- 2. ) Kuroishi , T. , Hirose , K. , Tominaga , S. , Ogawa , H. and Tajima , K.Prediction of future cancer mortality in Japan . Jpn. J. Clin. Oncol. , 22 , 365 – 369 ( 1992. ). [PubMed] [Google Scholar]
- 3. ) Nomura , A. , Henderson , B. and Lee , J.Breast cancer and diet among the Japanese in Hawaii . Am. J. Clin. Nutr. , 31 , 2020 – 2025 ( 1978. ). [DOI] [PubMed] [Google Scholar]
- 4. ) Hirayama , T.A large scale cohort study on cancer risks by diet—with special reference to the risk reducing effects of green‐yellow vegetable consumption . In“Diet, Nutrition and Cancer,” ed. Hayashi Y. , Nagao M. , Sugimura T. , Takayama S. , Tomatis L. , Wattenberg L. W. and Wogan G. N. , pp. 41 – 53 ( 1986. ). Japan Scientific Societies Press; , Tokyo . [PubMed] [Google Scholar]
- 5. ) Troll , W. , Wiesner , R. , Shellabarger , C. J. , Holtzman , S. and Stone , J. P.Soybean diet lowers breast tumor incidence in irradiated rats . Carcinogenesis , 1 , 469 – 472 ( 1980. ). [DOI] [PubMed] [Google Scholar]
- 6. ) Barnes , S. , Grubbs , C. , Setchell , K. D. R. and Carlson , J.Soybeans inhibit mammary tumors in models of breast cancer . In“Mutagen and Carcinogens in the Diet,” ed. Pariza M. W. , Aeschbacher H.‐U. , Felton J. S. and Sato S. , pp. 239 – 253 ( 1990. ). Wiley‐Liss; , New York . [PubMed] [Google Scholar]
- 7. ) Ito , A.Is miso diet effective for radiation injuries? Miso Sci. Technol. , 39 , 71 – 84 ( 1991. ) ( in Japanese ). [Google Scholar]
- 8. ) Watanabe , H. , Takahashi , T. and Ishimoto , T.The effect of miso diet on small intestinal damage in mice irradiated by X‐ray . Miso Sci. Technol. , 39 , 29 – 32 ( 1991. ) ( in Japanese ). [Google Scholar]
- 9. ) Walanabe , H. , Masaoka , Y. , Gotoh , T. , Fujimoto , N. and Ito , A.Effects of miso in reducing risk of liver and gastric tumors in experimental animals . In“Food Factors for Cancer Prevention,” ed. Ohigashi H. , Osawa T. , Terao J. , Watanabe S. and Yoshikawa T. , pp. 351 – 354 ( 1997. ). Springer‐Verlag; , Tokyo . [Google Scholar]
- 10. ) Gotoh , T. , Yamada , K. , Yin , H. , Ito , A. , Kataoka , T. and Dohi , K.Chemoprevention of N‐nitroso‐N‐methylurea‐induced rat mammary carcinogenesis by soy foods or bio‐chanin A . Jpn. J. Cancer Res. , 89 , 137 – 142 ( 1998. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. ) Masaoka , Y. , Watanabe , H. , Tanizaki , M. , Ando , Y. , Yamada , K. , Gotoh , T. , Fujimoto , N. and Ito , A.Effect of a miso diet on colonic aberrant crypt foci in F344 rats exposed to azoxymethane . In“Recent Advances in Gastroenterological Carcinogenesis I,” ed. Tahara E. , Sugimachi K. and Oohara T. , pp. 1181 – 1185 ( 1996. ). Monduzzi‐Editore; , Bologna . [Google Scholar]
- 12. ) Ito , A. and Watanabe , H.Recent topics on miso in the aspect of biological role and primary prevention of cancer . Hiroshima J. Med. Sci. , 47 , 5 – 9 ( 1994. ) ( in Japanese ). [Google Scholar]
- 13. ) Messina , M. and Barnes , S.The role of soy products in reducing risk of cancer . J. Natl. Cancer Inst. , 83 , 541 – 546 ( 1991. ). [DOI] [PubMed] [Google Scholar]
- 14. ) Wang , H. J. and Murphy , P. A.Isoflavone content in commercial soybean foods . J. Agric. Food Chem. , 42 , 1666 – 1673 ( 1994. ). [Google Scholar]
- 15. ) Coward , L. , Barnes , N. C. , Setchell , K. D. R. and Barnes , S.The antitumor isoflavone, genistein and daidzein, in soybean foods of American and Asian diets . J. Agric. Food Chem. , 41 , 1961 – 1967 ( 1994. ). [Google Scholar]
- 16. ) Fukutake , M. , Takahashi , M. , Ishida , K. , Kawamura , H. , Sugimura , T. and Wakabayashi , K.Quantification of genistein and genistin in soybeans and soybean products . Food Chem. Toxicol. , 34 , 457 – 461 ( 1996. ). [DOI] [PubMed] [Google Scholar]
- 17. ) Hortobagyi , G. N.Overview of new treatments for breast cancer . Breast Cancer Res. Treat. , 21 , 3 – 13 ( 1992. ). [DOI] [PubMed] [Google Scholar]
- 18. ) Costa , A.Breast cancer chemoprevention . Eur. J. Cancer , 29A , 589 – 592 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 19. ) Tominaga , T. , Yoshida , K. , Shimozuma , K. , Hayashi , K. and Kosai , G.Effect of CGS 16949A plus tamoxifen on induced mammary tumors in rats . Eur. J. Cancer , 26 , 600 – 603 ( 1990. ). [DOI] [PubMed] [Google Scholar]
- 20. ) Anzano , M. A. , Byers , S. W. , Smith , J. M. , Peer , C. W. , Mullen , L. T. , Brown , C. C. , Roberts , A. B. and Sporn , M. B.Prevention of breast cancer in the rat with 9‐cis‐retinoic acid as a single agent and in combination with tamoxifen . Cancer Res. , 54 , 4614 – 4617 ( 1994. ). [PubMed] [Google Scholar]
- 21. ) Weckbecker , G. , Tolcsvai , L. , Stolz , B. , Pollak , M. and Bruns , C.Somatostatin analogue octreotide enhances the antineoplastic effects of tamoxifen and ovariectomy on 7,12‐dimethylbenz(a)‐anthracene‐induced rat mammary carcinomas . Cancer Res. , 54 , 6334 – 6337 ( 1994. ). [PubMed] [Google Scholar]
- 22. ) McCormick , D. L. , Rao , K. V. N. , Johnson , W. D. , Bowman‐Gram , T. A. , Steele , V. E. , Lubet , R. A. and Kelloff , G. J.Exceptional chemopreventive activity of low‐dose dehydroepiandrosterone in the rat mammary gland . Cancer Res. , 56 , 1724 – 1726 ( 1996. ). [PubMed] [Google Scholar]
- 23. ) Hochberg , R. B. and Rosner , W.Interaction of 16α‐[125I]iodo‐estradiol with estrogen receptor and other steroid‐binding proteins . Proc. Natl. Acad. Sci. USA , 77 , 328 – 332 ( 1980. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. ) Tominaga , T. , Nomura , Y. , Kobayashi , S. , Yayoi , E. , Wada , T. , Enomoto , K. , Iino , Y. and Mori , I.Estrogen receptor assay in human breast cancer tissue using 16α‐125I‐estradiol‐17β . Prog. Med. , 3 , 399 – 404 ( 1983. ). [Google Scholar]
- 25. ) Ratcliffe , W. A. , Carter , G. D. , Dowsett , M. , Hillier , S. G. , Middle , J. D. and Reed , M. J.Oestradiol assays: applications and guidelines for the provision of clinical biochemistry service . Ann. Clin. Biochem. , 25 , 466 – 483 ( 1988. ). [DOI] [PubMed] [Google Scholar]
- 26. ) Shinha , D. K. , Pazik , J. E. and Dao , T. L.Progression of rat mammary development with age and its relationship to carcinogenesis by a chemical carcinogen . Int. J. Cancer , 31 , 321 – 327 ( 1983. ). [DOI] [PubMed] [Google Scholar]
- 27. ) Cronkite , E. P. , Shellabarger , C. J. , Bond , V. P. and Lippincott , S. W.Studies on radiation‐induced mammary gland neoplasia in the rat . Radiat. Res. , 12 , 81 – 93 ( 1960. ). [PubMed] [Google Scholar]
- 28. ) Hirayama , T.Epidemiology of stomach cancer in Japan with special reference to the strategy for the primary prevention . Jpn. J. Clin. Oncol. , 14 , 159 – 168 ( 1984. ). [PubMed] [Google Scholar]
- 29. ) Messina , M. J. , Persky , V. , Setchell , K. D. R. and Barnes , S.Soy intake and cancer risk: a review of in vitro and in vivo data . Nutr. Cancer , 21 , 113 – 131 ( 1994. ). [DOI] [PubMed] [Google Scholar]
- 30. ) Adlercreutz , H. , Honjo , H. , Higashi , A. , Fotsis , T. , Hämäläinen , E. , Hasegawa , T. and Okada , H.Urinary excretion of lignans and isoflavonoid phytoestrogens in Japanese men and women consuming a traditional Japanese diet . Am. J. Clin. Nutr. , 54 , 1093 – 1100 ( 1991. ). [DOI] [PubMed] [Google Scholar]
- 31. ) 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. and Pike , M. C.Tofu and risk of breast cancer in Asian‐Americans . Cancer Epidemiol. Biomarkers Prev. , 5 , 901 – 906 ( 1996. ). [PubMed] [Google Scholar]
- 32. ) Akiyama , T. , Ishida , J. , Nakagawa , S. , Ogawara , H. , Watanabe , S. , Itoh , N. , Shibuya , M. and Fukami , Y.Genistein, a specific inhibitor of tyrosine‐specific protein kinases . J. Biol. Chem. , 262 , 5592 – 5595 ( 1987. ). [PubMed] [Google Scholar]
- 33. ) Okura , A. , Arakawa , H. , Oka , H. , Yoshinari , T. and Monden , Y.Effect of genistein on topoisomerase activity and the growth of [VAL 12]H‐ras‐transformed NIH3T3 cells . Biochem. Biophys. Res. Commun. , 157 , 183 – 189 ( 1988. ). [DOI] [PubMed] [Google Scholar]
- 34. ) Fotsis , T. , Pepper , M. , Adlercreutz , H. , Hase , T. A. , Montesano , R. and Schweigerer , L.Genistein, a dietary ingested isoflavone, inhibits cell proliferation and in vitro angiogenesis . J. Nutr. , 125 , 790 – 797 ( 1995. ). [DOI] [PubMed] [Google Scholar]
- 35. ) Yanagihara , K. , Ito , A. , Toge , T. and Numoto , M.Anti‐proliferative effects of isoflavones on human cancer cell lines established from the gastrointestinal tract . Cancer Res. , 53 , 5815 – 5821 ( 1993. ). [PubMed] [Google Scholar]
- 36. ) Yanagihara , K. , Numoto , M. , Tauchi , H. , Akama , Y. , Yokozaki , H. , Tahara , E. , Kamiya , K. and Seito , T.Genetic status of p53 and induction of apoptosis by radiation or isoflavones in human gastric carcinoma cell lines . Int. J. Oncol. , 9 , 95 – 102 ( 1996. ). [DOI] [PubMed] [Google Scholar]
- 37. ) Matsukawa , Y. , Marui , N. , Sakai , T. , Satomi , Y. , Yoshida , Y. , Matsumoto , K. , Nishino , H. and Aoike , A.Genistein arrests cell cycle progression at G2‐M . Cancer Res. , 53 , 1328 – 1331 ( 1993. ). [PubMed] [Google Scholar]
- 38. ) Martin , P. M. , Horwitz , K. B. , Ryan , D. S. and McGuire , W. L.Phytoestrogen interaction with estrogen receptors in human breast cancer . Endocrinology , 103 , 1860 – 1867 ( 1978. ). [DOI] [PubMed] [Google Scholar]
- 39. ) Shutt , D. A. and Cox , R. I.Steroid and phyto‐estrogen binding to sheep uterine receptors in vitro . J. Endocrinol. , 52 , 299 – 310 ( 1972. ). [DOI] [PubMed] [Google Scholar]
- 40. ) Mathieson , R. A. and Kitts , W. D.Binding of phyto‐estrogens and estradiol‐17β by cytoplasmic receptors in the pituitary gland and hypothalamus of the ewe . J. Endocrinol. , 85 , 317 – 325 ( 1980. ). [DOI] [PubMed] [Google Scholar]
- 41. ) Folman , Y. and Pope , G. S.The interaction in the immature mouse of potent oestrogens with coumestrol, genistein and other utero‐vaginotrophic compounds of low potency . J. Endocrinol. , 34 , 215 – 225 ( 1966. ). [DOI] [PubMed] [Google Scholar]
- 42. ) Lu , L‐J. W. , Anderson , K. E. , Grady , J. J. and Nagamani , M.Effect of soya consumption for one month on steroid hormones in premenopausal woman: implication for breast cancer risk reduction . Cancer Epidemiol. Biomarkers Prev. , 5 , 63 – 70 ( 1996. ). [PubMed] [Google Scholar]
- 43. ) Kaplanski , O. , Shemesh , M. and Berman , A.Effects of phyto‐estrogens on progesterone synthesis by isolated bovine granulosa cells . J. Endocrinol. , 89 , 343 – 348 ( 1981. ). [DOI] [PubMed] [Google Scholar]
- 44. ) Gangrade , B. K. , Davis , J. S. and May , J. V.A novel mechanism for the induction of aromatase in ovarian cells in vitro: role of transforming growth factor α‐induced protein tyrosine kinase . Endocrinology , 129 , 2790 – 2792 ( 1991. ). [DOI] [PubMed] [Google Scholar]
- 45. ) Makela , S. , Davis , V. L. , Tally , W. C. , Korkman , J. , Salo , L. , Vihko , R. , Santti , R. and Korach , K. S.Dietary estrogens act through estrogen receptor‐mediated processes and show no antiestrogenicity in culture breast cancer cells . Environ. Health Perspect. , 102 , 572 – 578 ( 1994. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46. ) Campbell , D. R. and Kurzer , M. S.Flavonoid inhibition of aromatase enzyme activity in human preadipocytes . J. Steroid Biochem. Mol. Biol. , 46 , 381 – 388 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 47. ) Pike , M. C. , Spicer , D. V. , Dahmoush , L. and Press , M. F.Estrogens, progestogens, normal breast cell proliferation, and breast cancer risk . Epidemiol. Rev. , 15 , 17 – 35 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 48. ) Lazenby , C. , Westwood , F. R. and Greaves , P.Crescentic cataracts in Alderley Park rats . Vet. Pathol. , 30 , 70 – 74 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 49. ) Greaves , P. , Goonetilleke , R. , Nunn , G. , Topham , J. and Orton , T.Two‐year carcinogenicity study of tamoxifen in Alderley Park Wistar‐derived rats . Cancer Res. , 53 , 3919 – 3924 ( 1993. ). [PubMed] [Google Scholar]
- 50. ) Jaiyesimi , J. A. , Buzdar , A. U. , Decker , D. A. and Hortobagyi , G. N.Use of tamoxifen for breast cancer: twenty‐eight years later . J. Clin. Oncol. , 13 , 513 – 529 ( 1995. ). [DOI] [PubMed] [Google Scholar]
- 51. ) Jordan , V. C.Effect of tamoxifen (ICI 46,474) on initiation and growth of DMBA‐induced rat mammary carcinoma . Eur. J. Cancer , 12 , 419 – 424 ( 1976. ). [DOI] [PubMed] [Google Scholar]
- 52. ) Tucker , M. J.The effect of long‐term food restriction on tumors in rodents . Int. J. Cancer , 23 , 803 – 807 ( 1979. ). [DOI] [PubMed] [Google Scholar]
- 53. ) Birt , D. F. , Pelling , J. C. , White , L. T. , Dimitroff , K. and Barnett , T.Influence of diet and calorie restriction on the initiation and promotion of skin carcinogenesis in the Sencar mouse model . Cancer Res. , 51 , 1851 – 1854 ( 1991. ). [PubMed] [Google Scholar]
- 54. ) Gillette , C. A. , Zhu , Z. , Westerlind , K. C. , Melby , C. L. , Wolfe , P. and Thompson , H. J.Energy availability and mammary carcinogenesis: effects of calorie restriction and exercise . Carcinogenesis , 18 , 1183 – 1188 ( 1997. ). [DOI] [PubMed] [Google Scholar]
- 55. ) Osborne , M. P. , Ruperto , J. F. , Crowe , J. P. , Rosen , P. P. and Telang , N. T.Effect of tamoxifen on preneoplastic cell proliferation in N‐nitroso‐N‐methylurea‐induced mammary carcinogenesis . Cancer Res. , 52 , 1477 – 1480 ( 1992. ). [PubMed] [Google Scholar]
- 56. ) Taylor , I. W. , Hodson , P. J. , Green , M. D. and Sutherland , R. L.Effects of tamoxifen on cell cycle progression of synchronous MCF‐7 human mammary carcinoma cells . Cancer Res. , 43 , 4007 – 4010 ( 1983. ). [PubMed] [Google Scholar]
- 57. ) Sutherland , R. L. , Green , M. D. , Hall , R. E. , Reddel , R. R. and Taylor , I. W.Tamoxifen induces accumulation of MCF‐7 human mammary carcinoma cells in the G0/G1 phase of the cell cycle . Eur. J. Cancer Clin. Oncol. , 19 , 615 – 621 ( 1983. ). [DOI] [PubMed] [Google Scholar]
- 58. ) Osborne , C. K. , Boldt , D. H. , Clark , G. M. and Trent , J. M.Effect of tamoxifen on human breast cancer cell cycle kinetics: accumulation of cells in early G1 phase . Cancer Res. , 43 , 3583 – 3586 ( 1983. ). [PubMed] [Google Scholar]