Soybean isoflavones inhibit estrogen-stimulated gene expression in mouse uteri

This study was performed to examine the inhibitory effects of soybean isoflavones on estrogen-stimulated gene expression of the uteri in ovarectomized mice. Especially when compared with the inhibitory effect of genistein and daidzein as aglycosides described in our previous report, subcutaneous administration of the glycoside genistin significantly decreased the levels of estradiol-17beta (E2)-induced expressions of c-jun, interleukin (IL)-1alpha and tumor necrosis factor (TNF)-alpha mRNAs (p < 0.005, p < 0.05 and p < 0.05, respectively) and seemingly proteins in the mice uteri, whereas the glycoside daidzin weakly inhibited E2-stimulated expressions of c-fos and IL-1alpha. Both genistin and daidzin seemed to have a weaker inhibitory effect than that of genistein and daidzein on the expression of estrogen-stimulated genes. It is suggested that those glycosides are naturally derived and generally absorbed from plant foods and might prevent E2-related endometrial carcinogenesis.

Soybean isoflavones; c-fos/jun; IL-1 a, TNF-α

[1] Lian Z., Niwa K., Takami K., Hashimoto M., Gao J., Yokoyama Y. et al.: "Preventive effects of isoflavones, genistein and daidzein, on estradiol-17β-related endometrial carcinogenesis in mice". Jpn. J. Cancer Res., 2001, 92, 726.

[2] Onozawa M., Kawamori T., Baba M., Fukuda K., Toda T., Sato, H. et al.: "Effects of soybean isoflavone mixture on carcinogenesis in prostate and seminal vesicles of F344 rat". Jpn. J. Cancer Res., 1999, 90, 393.

[3] Wei H., Browen R., Zhang X., Lebwohl M. et al.: "Isotlavone genistein inhibits the initiation and promotion of two-stage skin carcinogenesis in mice". Carcinogenesis, 1998, 19, 1509.

[4] Hsieh C. Y., Santell R. C., Haslam S. Z., Helferich W. G. et al.: "Estrogenic effects of genistein on the growth of estrogen receptor-positive human breast cancer (MCF-7) cells in vitro and in vivo". Cancer Res., 1998, 58, 3833.

[5] Kato K., Takahashi S., Cui L., Toda T., Suzuki S., Futakuchi M. et al.: "Suppressive effects of dietary genistin and daidzin on rat prostate carcinogenesis". Jpn. J. Cancer Res., 2000, 91, 786.

[6] Fukutake M., Takahashi M., Ishida K., Kawamura H., Sugimura T., Wakabayashi K. et al.: "Quantification of genistein and genistin in soybeans and soybean products". Food Chem. Toxicol., 1996, 34, 457.

[7] Giri A. K., Lu L-J, W.: "Genetic damage and the inhibition of 7, 12-dimethylbenz [a] anthracene-induced genetic damage by the phytoestrogens, genistein and daidzein, in female ICR mice". Cancer Lett., 1995, 95, 125.

[8] Chomczynski P., Sacchi N. et al.: "Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction". Anal. Biochem., 1987, 162, 156.

[9] Weitz A., Bresciani F.: "Estrogen induces expression of c-fos and c-myc protooncogenes in the rat uterus". Mo/. Endocrionol., 1988, 2, 816.

[10] Weatz A., Cicatiello L., Persiot E., Scalona M., Bresciani F. et al.: "Estrogen stimulation of transcription of c-jun protooncogene". Mol. Endocrionol., 1990, 4, 1031.

[11] Lomedico P.T., Gubler U., Hellmann C.P., Dukovich M., Giri J. G., Pan Y.C. et al.: "Cloning and expression murine interleukin-I cDNA in Escherichia coli". Nature, 1984, 312, 458.

[12] Fransen L., Muller R., Marmenout A., Tavernier J., Van der Heyden J., Kawashima E. et al.: "Molecular cloning of mouse tumor necrosis factor cDNA and its eukaryotic expression". Nucl. Aci. Res., 1985, 13, 417.

[13] Sabath D., Broome H.E., Prystowsky M.B.: "mRNA is a maJor interleukin 2-induced transcript in a cloned T-helper lymphocyte". Gene, 1990, 91, 185.

[14] Niwa K., Hashimoto M., Morishita S., Lian Z., Tagami K., Mori H.: "Preventive effects of Juzen-taiho-to on N-methyl-Nnitrosourea and estradiol-17􀂫-induced endometrial carcinogenesis in mice". Carcinogenesis, 2001, 22, 587.

[15] Niwa K., Murase T., Furui T., Morishita S., Tanaka T., Mori H. et al.: "Enhancing effects of estrogens on endometrial carcinogenesis initiated by N-methyl-N-nitrosourea in ICR mice". Jpn. J. Cancer Res., 1993, 84, 951.

[16] Morishita S., Niwa K., Ichigo S., Hori M., Murase T. Fujimoto J. et al.: "Overexpressions of c-fos/jun mRNA and their oncoproteins (Fos/Jun) in the mouse uterus treated with three natural estrogens". Cancer Lett., 1995, 97, 225.

[17] Lian Z., Niwa K., Gao J., Tagami K., Hashimoto M., Yokoyama Y. et al.: "Shimotsu-to is the agent in Juzen-taiho-to responsible for the prevention of endometrial carcinogenesis in mice". Cancer Lett., 2002, 182, 19.

[18] Castrilli G., Tatone D., Diodoro M.G., Rosini S., Piantelli M., Musiani P. et al.: "Interleukin I alpha and interleukin 6 promote the in vitro growth of both normal and neoplastic human cervical epithelial cells". Brit. J. Cancer, 1997, 75, 855.

[19] Suganuma M., Okabe S., Marino M.W., Sakai A., Sueoka E., Fujiki H. et al.: "Essential role of tumor necrosis factor alpha (TNF-alpha) in tumor promotion as revealed by TNF-alpha-deficient mice". Cancer Res., 1999, 59, 4516.

[20] Fujiki H., Suganuma M., Okabe S., Sueoka E., Suga K., Imai K. et al.:''A new concept of tumor promotion by tumor necrosis factoralpha, and cancer preventive agents (-)-epigallocatechin gallate and green tea--a review". Cancer Dete. Preven., 2000, 24, 91.

[21] Suganuma M., Okabe S., Sueoka E., Iida N., Komori A., Kim S. J. et al.: "A new process of cancer prevention mediated through inhibition of tumor necrosis factor expression". Cancer Res., 1996, 56, 3711.

[22] Hur H.G., Lay J.O. Jr, Beger R.D., Freeman J.P., Rafii F. et al.: "Isolation of human intestinal bacteria metabolizing the natural isoflavone glycosides daidzin and genistin". Arch Microbial., 2000, 174, 422.