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Research Studying the Effect of Soybean Diets on Mammary Tumors in Rats

Compiled by Debbie “The Rat Lady” Ducommun

 

Most of the research done on the influence of diets containing soybean protein on the development of mammary tumors in rats has been done on mammary tumors experimentally induced in the rats.  A chemical called methylnitrosourea (MNU) reliably produces cancerous mammary tumors in rats when injected.  So does radiation with x-rays. These rats can then be used to test various ways to treat or prevent the tumors.  These studies can be done in a matter of weeks, while doing the same studies on spontaneous mammary tumors would require at least 2 or more years, since most rats don’t start growing natural mammary tumors until they are at least 18-24 months old.  In addition, because most of these studies are interested in finding a treatment or prevention of mammary cancer in humans, the rats with induced mammary cancer provide a better model than rats with spontaneous mammary tumors, most of which are benign and not cancerous.

 

However, a few studies have shown that the same factors that tend to reduce the formation or growth of induced mammary tumors, also tend to reduce the formation of spontaneous tumors.   The first two studies listed here mention spontaneous tumors.

 

http://carcin.oxfordjournals.org/cgi/content/abstract/1/6/469

Soybean diet lowers breast tumor incidence in irradiated rats, Troll, W. et al. Carcinogenesis  1980; 1: 469-72

This paper examines the relationship between feeding a diet rich in protease inhibitors and the reduction of mammary cancer induced by x-irradiation in Sprague-Dawley rats. Of a total of 145 irradiated animals, 44% of the 45 rats fed a raw soybean diet containing a high concentration of protease inhibitor developed mammary tumors as compared to 74% of 50 rats fed a casein diet containing no protease inhibitor. Animals fed Purina rat chow which contained low levels of protease inhibitor exhibited a 70% mammary tumor incidence. No spontaneous neoplasms were found in any of the non-irradiated animals on the raw soybean diet whereas about 10% of the animals on the protease-free diet developed tumors. (emphasis added) Thus, soybeans which are rich in protease inhibitors reduced the induction of mammary cancer in x-irradiated rats. This work suggests that diets rich in protease inhibitors may contribute to reducing cancer incidence in man.

Troll, W.  Soybean diet lowers breast tumor incidence in irradiated rats. 

 

http://jn.nutrition.org/cgi/content/full/131/12/3281

Soy and Whey Proteins Downregulate DMBA-Induced Liver and Mammary Gland CYP1 Expression in Female Rats. J. Craig Rowlands, Ling He, Reza Hakkak, Martin J. J. Ronis and Thomas M. Badger.  Journal of Nutrition. 2001;131:3281-3287.

From the Discussion section:

Previous studies have reported that the incidence of either spontaneous mammary tumors

(23Citation ) or chemically-induced mammary tumors are lower in rats fed diets made with soy flour or soy protein isolate (24Citation –28Citation ).

 

23. Troll, W., Belman, S., Wiesner, R. & Shellabarger, C. J. (1979) Protease action in carcinogenesis. Holzer, H. Tschasche, H. eds. Biological Function of Proteinases 1979:165-170 Springer-Verlag Berlin. (Unfortunately, I have not been able to find the abstract or text of this study.)

 

Other studies cited in this article included the following:

24. Barnes, S., Grubbs, C., Setchell, K. D. & Carlson, J. (1990) Soybeans inhibit mammary tumors in models of breast cancer. Prog. Clin. Biol. Res. 347:239-253.[Medline]

25. 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.

27. Zaizen, Y., Higuchi, Y., Matsuo, N., Shirabe, K., Tokuda, H. & Takeshita, M. (2000) Antitumor effects of soybean hypocotyls and soybeans on the mammary tumor induction by N-methyl-n-nitrosourea in F344 rats. Anticancer Res 20:1439-1444.[Medline]

28. 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.[Medline]

 

http://carcin.oxfordjournals.org/cgi/content/full/28/5/1046

In utero exposure to maternal diets containing soy protein isolate, but not genistein alone, protects young adult rat offspring from NMU-induced mammary tumorigenesis, Ying Su, Renea R. Eason, Yan Geng, SR Till, Thomas M. Badger and Rosalia C.M. Simmen, Carcinogenesis, 2007 28(5):1046-1051.

This has exciting implications!  It means that mother rats fed a diet high in soybean protein might have daughters less likely to have mammary tumors.

Abstract (Full text online):

The linkage of nutrition and cancer prevention is an intriguing concept that is gaining widespread support. Here, we investigated the influence of developmental context on dietary protection against tumorigenesis initiated by the direct-acting carcinogen N-methyl-N-nitrosourea (NMU), and examined potential mechanisms underlying these effects. Rats were exposed only in utero or for lifetime to American Institute of Nutrition-93G diets made with casein (CAS), soy protein isolate (SPI) or CAS supplemented with genistein (GEN). Mammary glands of post-natal day (PND) 50 rats prior to NMU administration were examined for apoptotic status, pro-apoptotic gene expression and immunoreactive phosphatase and tensin homolog deleted on chromosome ten (PTEN) and epithelial cadherin (E-cadherin) levels, whereas mammary tumor parameters were evaluated 99 days post-NMU. Animals exposed only in utero to SPI had increased tumor latency, decreased tumor multiplicity and lower higher grade tumors, than those fed CAS. In utero exposure to GEN resulted in similar tumor parameters as the CAS group, whereas lifetime SPI exposure decreased tumor incidence that was not mimicked by in utero exposure alone. Mammary glands of PND50 rats fed lifetime SPI had increased terminal end bud apoptotic status and PTEN expression, than the other diet groups. Rats exposed only in utero to SPI or GEN had higher membrane E-cadherin in mammary structures than those lifetime-fed CAS or SPI. Thus, limited exposure during gestation to SPI can positively influence resistance to chemically induced mammary tumorigenesis later in life. Preventative strategies against mammary and other types of cancer might be uncovered by refinement of the developmental window for dietary factor exposure.

 

 

Chemoprevention and chemotherapeutic potentials upon MNU induced mammary carcinomas (MCA) by a combination of miso and tamoxifen.  Ito, A. et al.  Research Inst. Of Radiation Biology and Medicine, Hiroshima Univ.  Abstract in Proceedings of the American Association for Cancer Research, March 1997, Volume 38, page 369

Aim: A single administration of either miso (fermented soybean paste), soybean, or biochanin A (isoflavone) was quite inhibitory for the occurrence of rat MCA induced by MNU.  The present study was undertaken to evaluate a combination effect of miso and tamoxifen for the 1) primary prevention of MNU induced mammary tumors, and 2) chemo-therapeutic trials for manifested MNU induced mammary tumors (1.5 to 2.0 cm in average size).  Results: 1. Continuous administration of either miso or tamoxifen in rats treated with MNU was significantly inhibitory for the occurrence of mammary carcinomas.  2. a combinational treatment of miso and tamoxifen was almost completely inhibitory for the occurance of MCA.  3. Averaged sizes of 1.5 to 2.0 cm mammary tumors were treated with a combination of tamoxifen and 2%, 5%, or 10% miso containing diet, and growth of MCA was reduced dose dependently with the % of miso.  4. Possible preventive mechanisms of miso for the development of mammary tumors could be explained by the findings: 1) up-regulation of estrogen receptor levels of MCA, and 2) immunological reactions around MCA tissues treated with miso diet.

 

 

A combined effect of tamoxifen and miso for the development of mammary tumors induced with MNU in SD rats.  Ito, A. et al.  Research Inst. For Radiation Biol. & Med., Hiroshima Univ., April 21, 1996, Poster Section 16.  Abstract in the Proceedings of the American Association for Cancer Research, vol 37, March 1996.

Seven-week-old SD rats were once IV injected with 50 mg/kg of MNU.  Within a week, rat were fed with chow diets containing 2% or 10% soybean, 10% miso (a fermented soybean paste), 10 mg or 50 mg/kg biochanin A (BCA, a isoflavone) in food for 18 weeks in separate groups.  Incidence and multiplicity of mammary tumors (exclusively carcinomas) wer highest in controls by 90% (percentage of rats with tumors) and 4.54 (average number of tumors per rat), 83% and 2.22* in the 2% soybean group, 72% and 1.83* in the 10% soybean group, 75% and 1.40** in the 10% miso group, 89% and 2.10* in the 10 mg BCA group, and 68% and 2.36* in the 50 mg BCA group. In the similar experimental schedule, rats were implanted s.c. with a 2.5 mg tamoxifen-containing cholesterol pellet (TAM), renewed once 5 weeks later, or a combination of a 10% miso diet and TAM.  Tumor incidence and multiplicity were 68% and 1.40* in the TAM group, and only 4.8% and 0.14** in the combo group.  The results indicated that miso and it constituents of soybean or BCA were significantly inhibitory for the average number of mammary tumors.  In addition, the combination of TAM and miso was significantly inhibitory for both the incidence and number of mammary tumors.

(* significant from control by p<0.05, **significant from control by p<0.01)

 

 

http://jn.nutrition.org/cgi/content/abstract/121/10/1693

Dietary Soybean Isolate and Methionine Supplementation Affect Mammary Tumor Progression in Rats, E. J. Hawrylewicz, H. H. Huang and W. H. Blair, The Journal of Nutrition, Manuscript received 30 October 1990. Revision accepted 26 March 1991.

 

The effect of feeding soybean protein isolate (SBP) diet or soybean protein isolate diet supplemented with 0.7% DL-methionine (SBP+Met) on mammary tumor progression was investigated. Sprague-Dawley female rats were fed from weaning a 20% casein (CAS) diet supplemented with 0.3% DL-methionine (AIN-76) and injected via jugular vein with N-nitrosomethylurea (NMU, 40 mg/kg body weight) at 7 wk of age. Five weeks after NMU treatment, animals were divided into the three isoenergetic, isoprotein diet groups: CAS (25 rats); SBP (26 rats) and SBP+Met (25 rats). First palpable mammary tumors were evident 8, 9 and 13 wk and the mean latency period was 13.30 ± 1.23, 16.70 ± 1.32 and 17.82 ± 1.28 wk after NMU treatment in the CAS, SBP+Met and SBP diet groups, respectively. Tumor incidence was 80% in the CAS group compared with 42.3% in the SBP group (P = 0.01). Methionine supplementation increased tumor incidence to 64%. Total number and total weight of tumors was greater in the CAS group compared with either SBP+Met or SBP groups: 41 vs. 28 or 21 tumors and 97.28 g vs. 27.87 or 32.46 g, respectively. These data indicate that SBP diet, low in methionine content, fed 5 wk after carcinogen exposure significantly repressed mammary tumor progression. Methionine supplementation increased the number of animals with tumors but not the mean tumor weight.

 

http://www.ncbi.nlm.nih.gov/pubmed/11759821

Chemoprevention of DMBA-induced mammary cancer in rats by dietary soy.

Gallo, D, et al. Breast Cancer Res Treat.

 2001 Sep;69(2):153-64.

This study was designed to assess the potential chemopreventive effect of the administration of a standardized soy extract, SOYSELECT, on 7,12-Dimethylbenz[a]anthracene (DMBA)-induced mammary tumors in rats. Three groups, 24 females each, were used. Animals were fed either a phytoestrogen-free diet alone (control) or the same diet supplemented with 0.35% or 0.7% of soy extract. Treatment started at weaning and continued to the end of the study (24 weeks after DMBA administration). At day 50 of age all animals received via oral gavage 80 mg/kg DMBA. Only tumors subsequently classified as adenocarcinomas were considered for data evaluation. In rats on the soy diet, mammary tumors took a longer period of time to develop as compared to control rats. However, at the end of the study, no relevant difference in tumor incidence and multiplicity was observed among the groups. The most significant changes were seen between control and soy-treated groups when tumor dimension and results from histopathologic examination were considered. The latter, in fact, showed a dose-dependent reduction in the percentage of poorly differentiated tumors in treated animals. This change was statistically significant in animals receiving 0.7% soy. In addition, assessment of estrogen and progesterone receptor (ERalpha, PR) levels, revealed a significant reduction in the percentage of ERalpha and PR positive tumors in animals receiving 0.7% dietary soy, when compared to controls. Interestingly, genistein and daidzein plasma levels determined at the end of the study were within the range of those detected in people consuming large amounts of soyfoods.

 

http://www.stratsoy.uiuc.edu/expert/ffh.html#food3

The effect of soybean protein, low methionine, diet on the histopathology of recurrent mammary tumors.  E.J. Hawrylewicz, W.H. Blair, J.J. Zapata, H.H. Huang, Mercy Hospital and Medical Center, Chicago, IL, Presented at the First International Symposium on the role of Soy in Preventing and Treating Chronic Disease, February 20-23, 1994, Mesa, Arizona.

ABSTRACT

We reported that a soybean protein (SBP) diet, low in essential methionine, significantly delayed mammary tumor (MT) progression in the adult rat without any effect on body weight. Present study determined the effect of SBP diet on recurrence of MT after excision of the primary tumor. After weaning, S/D female rats (N=75) were fed casein, 20% (C) diet. NMU (N-nitrosomethylurea, 55mg/kg B.W.) was administered at 7 wks of age. Primary MT was excised and rats randomly placed into diet groups: (C), SBP-19% or SBP-38%. Four weeks after excision of the primary MT, 83.3% of the animals in group C had MT recurrence. Only 23% occurred in SBP-19% and 43.5% in SBP-33% groups. Total number of recurrent MT in each diet group: C, SBP-19% and SBP 33% was 128, 53 and 98 respectively. Total weight of recurrent MT in each diet group: C, SBP-19%, SBP-33% was 221.9g, 110.9g and 221.3g respectively. Coded tumor sections were evaluated histopathologically. Eighty-six percent of the primary MT were classified as adenocarcinoma with the most aggressive characteristics (Grades 3 and 2+). Recurrent tumors were classified as follows: C, Grades 3 and 2+, 45.56k (N=36), and fibroadenoma, 7.59W (N=6). In contrast, group SBP=19%, Grades 3 and 2+, 26.47% (N=9) and fibroadenoma 20.58% (N=7). Group SBP-33%, Grades 3 and 2+, 29.16% (N=21) and fibroadenoma 25% (N=18). The results indicate that methionine deficient soybean protein diet significantly inhibited mammary tumor recurrence and histopathologic development without altering food consumption or body weight of the animal.

 

http://carcin.oxfordjournals.org/cgi/content/full/21/5/937

Inhibitory effects of Bifidobacterium-fermented soy milk on 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine-induced rat mammary carcinogenesis, with a partial contribution of its component isoflavones.  Toshihisa Ohta, et al. Carcinogenesis, Vol. 21, No. 5, 937-941, May 2000

Abstract (Full text online):

High consumption of soybean and soybean-related products is hypothesized to contribute to protection against breast cancer. Soybean is a rich source of genistein, a putative cancer chemopreventive agent. Fermented soy milk (FSM), which is made of soy milk fermented with the Bifidobacterium breve strain Yakult, contains larger amounts of the isoflavone aglycones genistein and daidzein than unfermented soy milk. In the present study, we examined the effects of FSM and its component isoflavone mixture (genistein:daidzein 4:1) on 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced mammary carcinogenesis in rats. Starting at 7 weeks of age, female Sprague–Dawley rats were given PhIP at a dose of 85 mg/kg body wt by intragastric administration four times a week for 2 weeks. They were fed control high fat basal diet or experimental high fat diet containing 10% FSM or 0.02 or 0.04% isoflavone mixture during and after carcinogen exposure. The incidences (percentage of rats with tumors) of mammary gland tumors were 71% in the control diet group, 51% in the FSM group and 68 and 61% in the groups treated with isoflavone mixture at 0.02 and 0.04%, respectively. Mammary tumor multiplicities (number of tumors per rat) were 1.2 ± 0.2 for 10% FSM, 2.2 ± 0.4 for 0.02% isoflavone mixture and 1.5 ± 0.3 for 0.04% isoflavone mixture, being clearly smaller than the control diet value (2.6 ± 0.5). Furthermore, feeding of FSM and the isoflavone mixture at both doses reduced the sizes of mammary tumors. Since the amounts of isoflavones in 10% FSM are approximately equivalent to those in the 0.02% isoflavone mixture, the chemopreventive activity of FSM could be partly attributable to the presence of isoflavones such as genistein and daidzein.

 

 

Soybeans inhibit mammary tumor growth in models of breast cancer. Barnes, S, in Mutagens and Carcinogens in the Diet, ed. M.W. Pariza, New York: Wiley-Liss, 1990.

 

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