Biphasic effects of kaempferol on the estrogenicity in human breast cancer cells

  • Seung Min Oh
  • Yeon Pan Kim
  • Kyu Hyuck Chung
Articles Drug Design


Dietary flavonoids have attracted a great deal of attention as agents for preventing estrogen-related diseases, such as postmenopausal symptoms, and for reducing the risk of estrogen-dependent cancer. Kaempferol is one of the most commonly found dietary phytoestrogen. The aim of this study was to investigate the estrogenic and/or antiestrogenic effect of kaempferol, which can confirm its potency as a preventive agent against estrogen-related diseases. Kaempferol has both estrogenic and antiestrogenic activity, which are biphasic response on estrogen receptor. The estrogenic activity of kaempferol inducedvia ER-mediated pathway depending on E2 concentration (≤10−12 M). Kaempferol (10−5 M) also caused antiproliferative effect on MCF-7 cell in the presence of E2 (10−11 M) and restored to the addition of excess E2 (10−7 M), which confirms that antiproliferation of kaempferol was induced via ER-dependent pathway. However, at 10−4 M, concentration higher than the concentrations at which the estrogenic effects of kaempferol are detected (10−5 M), kaempferol induced strong antiproliferative effect, but were unaffected by the addition of excess E2 (10−7 M) indicating that kaempferol exerts antiproliferation via ER-independent pathway. In particular, kaempferol blocked the focus formation induced by E2, which confirms that kaempferol might inhibit the malignant transformation caused by estrogens. Therefore, we suggested that kaempferol might regulate a suitable level of estrogenic activity in the body and is expected to have potential beneficial effects in preventing estrogen imbalance diseases (breast cancer, osteoporosis, cardiovascular disease and etc.).

Key words

Kaempferol (Anti-)estrogenic activity Chemopreventive effect 


  1. Arcaro, K. F., Vakharia, D. D., Yang, Y., and Gierthy, J. F., Lack of synergy by mixtures of weakly estrogenic hydroxylated polychlorinated biphenyls and pesticides.Environ Health Perspect., 106 (Suppl. 4), 1041–1046 (1998).PubMedCrossRefGoogle Scholar
  2. Basly, J. P., Marre-Fournier, F., Le Bail, J. C., Habrioux, G., and Chulia, A. J., Estrogenic/antiestrogenic and scavenging properties of (E)- and (Z)-resveratrol.Life Sciences, 66(9), 769–777 (2000).PubMedCrossRefGoogle Scholar
  3. Birt, D. F., Hendrich, S., and Wang, W., Dietary agents in cancer prevention: flavonoids and isoflavonoids.Pharmacology & Therapeutics, 90, 157–177 (2001).CrossRefGoogle Scholar
  4. Brown, A. M. C., Jeltsch, J. M., Roberts, M., and Chambon, P., Activation of pS2 gene transcription is a primary response to estrogen in the human breast cancer cell line MCF-7.Proc. Natl Acad Sci., 81, 6344–6348 (1984).PubMedCrossRefGoogle Scholar
  5. Brzexinski, A. and Debi, A., Phytoestrogen: the “natural” selective estrogen receptor modulators?European Journal of Obstetrics & Gynecology and Reproductive Biology, 85, 47–51 (1999).CrossRefGoogle Scholar
  6. Ciocca, D. R. and Roig, L. M., Estrogen receptors in human nontarget tissues: biological and clinical implications.Endocrine Rev., 16, 35–62 (1995).CrossRefGoogle Scholar
  7. Ciolino, H. P., Daschner, P. J., and Yeh, G. C., Dietary flavonols quercetin and kaempferol are ligands of the aryl hydrocarbon receptor that affect CYP1A1 transcription differentially.Biochem J., 340, 715–722 (1999).PubMedCrossRefGoogle Scholar
  8. Cormier, E. M. and Jordan, V. C., Contrasting ability of antiestrogens to inhibit MCF-7 growth stimulated by estradiol or epidermal growth factor.European Journal of Cancer Clinical Oncology, 25, 57–63 (1989).PubMedCrossRefGoogle Scholar
  9. De Vries J. H., Hollman, P. C., Meyboom, S., Buysman, M. N., Zock, P. L., van Staveren W. A., and Katan, M. B., Plasma concentrations and urinary excretion of the antioxidant flavonols quercetin and kaempferol as biomarkers for dietary intake.Am J Clin Nutr., 68, 60–65 (1998).PubMedGoogle Scholar
  10. Fioravanti, L., Cappelletti, V., Miodini, P., Ronchi, E., Brivio, M., and Di Fronzo, G., Genistein in the control of breast cancer cell growth: insights into the mechanisms of actionin vitro.Cancer Letters, 130, 143–152 (1998).PubMedCrossRefGoogle Scholar
  11. Fotsis, T., Pepper, M. S., Aktas, E., Breit, S., Rasku, S., Adlercreuta, H., Wähälä, K., Montesano, R., and Schweigerer, L., Flavonoids, dietary-derived inhibitors of cell proliferation andin vitro angiogenesis.Cancer Research, 57, 2916–2921 (1997).PubMedGoogle Scholar
  12. Gierthy, J. F., Lincoin II, D. W., Roth, K. E., Bowser, S. S., Bennett, J. A., Bradley, L., and Dickerman, H. W., Estrogen-stimulation of postconfluent cell accumulation and foci formation of human MCF-7 breast cancer cells.J. Cellular Biochem., 45, 177–187 (1991).CrossRefGoogle Scholar
  13. Henderson, B. E., Ross, R., and Bernstein, L., Estrogens as a cause of human cancer: the Richard and Hinda Rosenthal Foundation award lecture.Cancer Res., 48, 246–253 (1988).PubMedGoogle Scholar
  14. Hsu, J. T., Hsu, W. L., and Ying, C., Dietary phytoestrogen regulates estrogen receptor gene expression in human mammary carcinoma cells.Nutrition Research, 19(10), 1447–1457 (1999).CrossRefGoogle Scholar
  15. Hung, H., Inhibition of estrogen receptor alpha expression and function in MCF-7 cells by kaempferol.Journal of cellular physiology, 198, 197–208 (2004).PubMedCrossRefGoogle Scholar
  16. Ingram, D., Sanders, K., Kolybaba, M., and Lopez, D., Case-control study of phytoestrogens and breast cancer.Lancet, 350, 990–9940 (1997).PubMedCrossRefGoogle Scholar
  17. Knowlden, J. M., Gee, J. M. W., Bryant, S., MeClelland, R. A., Manning, D. L., Mansel, R., Ellis, I. O., Blamey, R. W., Robertson, J. F. R., and Nicholson, R. I., Use of reverse transcription-polymerase chain reaction methodology to detect estrogen-regulated gene expression in small breast cancer specimens.Clinical Cancer Research, 3, 2165–2172 (1997).PubMedGoogle Scholar
  18. Kurzer, M. S. and Xu, X., Dietary phytoestrogens.Annu Rev Nutr., 17, 353–381 (1997).PubMedCrossRefGoogle Scholar
  19. Le Bail, J. C., Varnat, F., Nicolas, J. C., and Habrioux, G., Estrogenic and antiproliferative activities on MCF-7 human breast cancer cells by flavonoids.Cancer Letters, 130, 209–216. (1998).PubMedCrossRefGoogle Scholar
  20. Leung, L. K. and Wang, T. T., Bcl-2 is not reduced in the death of MCF-7 cells at low genistein concentration.J nutri., 130, 2922–2926. (2000).Google Scholar
  21. Leung, L. K., Po, L. S., Lau, T. Y., and Yuen, Y. M., Effect of dietary flavonols on oestrogen receptor transactivation and cell death induction.British Journal of Nutrition, 91, 831–839 (2004).PubMedCrossRefGoogle Scholar
  22. Macgregor J. I. and Jordan, V. C., Basic guide to the mechanisms of antiestrogen action.The American Society for Pharmacology and Experimental Therapeutics, 50(2), 151–196 (1998).Google Scholar
  23. Masiakowski, R., Breathnach, R., Bloch, J., Gannon, R., Krust, A., and Chambon, P., Cloning of cDNA sequences of hormone-regulated genes from the MCF-7, human breast cancer cell line.Nucleic Acids Res., 10, 7895–7903 (1982).PubMedCrossRefGoogle Scholar
  24. Messina, M., Barnes, S., and Setchell, K. D., Phytoestrogens and breast cancer-commentary.Lancet, 350, 971–972 (1997).PubMedCrossRefGoogle Scholar
  25. Nomoto, S., Arao, Y., Horiguchi, H., Ikeda, K., and Kayama, F., Oestrogen causes G2/M arrest and apoptosis in breast cancer MDA-MB-231.Oncol Rep., 9, 773–776 (2002).PubMedGoogle Scholar
  26. Oh, S. M. and Chung, K. H., Estrogenic activities of Ginkgo biloba extracts.Life sciences, 74, 1325–1335 (2004).PubMedCrossRefGoogle Scholar
  27. Olea, N., Pulgar, R., Perez, P., Olea-Serrano, F., Rivas, A., Novillo-Fertrell, A., Pedraza, V., Soto, A. M., and Sonnenschein, C., Estrogenicity of resin-based composites and sealants used in dentistry.Environ health Perspect., 104(3) 298–305 (1996).PubMedCrossRefGoogle Scholar
  28. Peeters, P. H. M., Keinan-Boker, L., van der Schouw, Y. T., and Grobbee, D. E., Phytoestrogens and breast cancer risk.Breast Cancer Research and Treatment, 77, 171–183 (2003).PubMedCrossRefGoogle Scholar
  29. Perez, P., Pulgar, R., Olea-Serrano, F., Villalobos, M., Rivas, A., Metzler, M., Pedraza, V., and Olea, N., The estrogenicity of bisphenol A-related diphenylalkanes with various substituents at the central carbon and the hydroxy groups.Environ Health Perspect., 106(3), 298–305. (1998).CrossRefGoogle Scholar
  30. Peterson, G. and Barnes, S., Genistein inhibition of the growth of human breast cancer cells: independent from estrogen receptors and the multi-drug resistance gene.Biochem Biophys Res Commun. 179, 661–667 (1991).PubMedCrossRefGoogle Scholar
  31. Po, L. S., Chen, Z-Y., Tsang, D. S. C., and Leung, L. K., Baicalein and genistein display differential actions on estrogen receptor (ER) transactivation and apoptosis in MCF-7 cells.Cancer Letters, 187, 33–34 (2002).PubMedCrossRefGoogle Scholar
  32. Pozo-Guisado, E., Alvarez-Barrientos, A., Mulero-Navarro, S., Santiago-Josefat, B., and Femandez-Salguero, P. M. The antiproliferation activity of resveratrol results in apoptosis in MCF-7 but not in MDA-MB-231 human breast cancer cells: cell-specific alterations of the cell cycle.Biochem Pharmacol., 54, 1375–1386 (2002).CrossRefGoogle Scholar
  33. Sathyamoorthy, N., Wang, T. T. Y., and Phang, J. M., Stimulation of pS2 expression by diet-derived compounds.Cancer Research, 54, 957–961 (1994).PubMedGoogle Scholar
  34. So, F. V., Guthrie, N., Chambers, A. F., and Carroll, K. K., Inhibition of proliferation of estrogen receptor-positive MCF-7 human breast cancer cells by flavonoids in the presence and absence of excess estrogen.Cancer Letters, 112, 127–133 (1997).PubMedCrossRefGoogle Scholar
  35. Strauss, L., Santti, R., Saarinen, N., Streng, T., Joshi, S., and Mäkelä, S., Dietary phytoestrogens and their role in hormonally dependent disease.Toxicology Letters, 102–103, 349–354 (1998).PubMedCrossRefGoogle Scholar
  36. This, P., De la Rochefordiere, A., Clough, K., Fourquet, A., and Magdelenat, H., Phytoestrogens after breast cancer.Endocrine-Related Cancer, 8, 129–134 (2001).PubMedCrossRefGoogle Scholar
  37. Upadhyay, S., Neburi, M., Chinni, S. R., Alhasan, S., Miller, F., and Sarkar, F. H., Differential sensitivity of normal and malignant breast epithelial cells to genistein is partly mediated by p21WAF1.Clin Cancer Res., 7, 1782–1789 (2001).PubMedGoogle Scholar
  38. Wang, T. T. Y., Sathyamoorthy, N., and Phang, J. M., Molecular effects of genistein on estrogen receptor mediated pathways.Carcinogenesis, 17, 271–275 (1996).PubMedCrossRefGoogle Scholar
  39. Wang, C. and Kurzer, M. S., Phytoestrogen concentration determines effects on DNA synthesis in human breast cancer cell.Nutr Cancer., 28(3), 236–247 (1997).PubMedCrossRefGoogle Scholar
  40. Yager, J. D. and Liehr, J. G., Molecular mechanisms of estrogen carcinogenesis.Ann Rev Pharmacol Toxicol., 36, 203–232 (1996).CrossRefGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea 2006

Authors and Affiliations

  • Seung Min Oh
    • 2
  • Yeon Pan Kim
    • 1
  • Kyu Hyuck Chung
    • 2
  1. 1.Meditech Korea PharmSeoulKorea
  2. 2.College of PharmacySungkyunkwan UniversitySuwonKorea

Personalised recommendations