January 7, 2014

Phytoestrogen Influence on ER+ Breast Cancer Cells


Sakamoto T, Horiguchi H, Oguma E, Kayama F. Effects of diverse dietary phytoestrogens on cell growth, cell cycle and apoptosis in estrogen-receptor-positive breast cancer cells. Journal of Nutritional Biochemistry, 2009 Oct 2nd (ahead of print)


In vitro

Key Findings

This study investigated the effects of estradiol, daidzein, genistein, coumestrol, resveratrol and glycitein on cell growth, cell cycle, cyclin D1 expression, apoptosis, Bcl-2/Bax expression ratio and p53-dependent or NF-kappaB-dependent transcriptional activity in MCF-7 breast cancer cells in an attempt to identify safe candidates for HRT and breast cancer prevention.
Coumesterol stimulates growth but not apoptosis, yet is found at such low doses in food and supplements that it is believed unlikely to increase the risk of breast cancer.
Coumesterol stimulates growth but not apoptosis, yet is found at such low doses in food and supplements that it is believed unlikely to increase the risk of breast cancer. Daidzein showed no antitumor activity in the absence of E2 and only a partial suppressive effect on E2-stimulated tumor growth while causing a slight cell-stimulating effect in the absence of E2 which could lead to an increased risk of breast cancer in postmenopausal women. Based upon these findings and research showing elevated serum concentrations of phytoestrogens in postmenapausal women taking daidzein supplements1, this research team feels supplementation may not be recommended. Genistein was similar to Daidzein in effect yet also induced apoptosis, showing a slight reduction in Bcl-2/Bax ratio yet upregulated both Bcl-2 and Bax. The Bcl-2/Bax ratio molecular mechanism was chosen for it is a marker for apoptosis via mitochondrial involvement when decreased. Glycitein repressed cell growth, induced apoptosis, slightly reduced the Bcl-2/Bax ratio and had a weaker effect on endogenous ER transactivation than the other phytoestrogens. Resveratrol repressed cell growth, induced apoptosis and significantly reduced the Bcl-2/Bax ratio (upregulated Bax but not Bcl-2) independent of the presence of E2. It enhanced P53 dependent transcriptional activity and slightly reduced NF-kB(beta) dependent transcriptional activity. The researchers felt this is the most promising candidate as a chemopreventive agent and HRT alternative. This is in part due to their search to understand whether cell cycle regulation or apoptosis was more important in regulating tumor growth. They observed a significant negative correlation between cell growth and apoptosis, a weak but not as significant with Bcl-2/Bax ratio while no correlation was observed with G1/S transition and little with expression of cyclin D1. They conclude by suggesting that apoptosis may be the leading factor in cell growth repression. It was also observed that genistein, resveratrol and glycitein exerted an apoptotic effect in the absence of ER and may use an ER-independent pathway. This study attempted to mimic doses that would be comparable to serum levels when taking a supplement by using higher pharmacological levels of phytoestrogens (10-5 M).

Practice Implications

This information is important in helping to determine some of the mechanisms of action phytoestrogens have on tumor cells and growth while attempting to address the issues of pre vs. post menopausal situations. The study shows that resveratrol is most impressive as a single agent compared to the other phytoestrogens studied. The questions remain on the controversy surrounding the use of phytoestrogens found in soy. This study refers to epidemiological studies from China, Japan and the Netherlands which suggest that soy intake is associated with a slight decrease in breast cancer, yet this study and others of the individual constituents appear to show the opposite. More research is needed on the synergistic effect of isoflavones in vitro and in vivo. A recent human study showed that seaweed plus soy favorably alters estrogen and phytoestrogen metabolism in postmenopausal women2. Although it was a small study of n=15, the insights given in studies like this are helping us to understand the synergistic effect of isoflavones as well as other dietary habits of societies and how we may apply this to benefit breast cancer patients.


This study chose to look at the individual effects of phytoestrogens compared to endogenous estradiol offering interesting data on the relative strength of the phytoestrogens. This study did not explore possible synergistic effects of the phytoestrogens.
For more research involving integrative oncology, click here.

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  1. Khaodhiar L, Ricciotti HA, Li L, Pan W, Schickel M, Zhou J, et al. Daidzein-rich isoflavone aglycones are potentially effective in reducing hot flashes in menopausal women. Menopause 2008;15:125–32.
  2. Teas J. et al. Dietary seaweed modifies estrogen and phytoestrogen metabolism in healthy postmenopausal women. J Nutr. 2009 May;139(5):939-44.