Decreased cell proliferation of breast cancer cells by genistein is caused by estrogen receptor related signaling molecules.
Authors: Stamschror J , Yaghmour E , Sorenson M , Ahmed S , Rajah TT 
Published: December 2010

Abstract
Abstract #6019
Background: Literature reports demonstrate that genistein, a soy phytoestrogen, shows a biphasic response to cell proliferation in breast cancer cells. Genistein increases cell proliferation at low concentrations and decreases cell proliferation at high concentrations. Our previous studies suggest that at low concentrations of genistein the cell proliferative response depends on the type of ER. At high concentrations genistein is believed to act as a tyrosine kinase inhibitor. Currently, the mechanisms of genistein's effect on breast cancer cell proliferation are unclear. The aim of this study was to evaluate the mechanisms of the biphasic response of genistein on breast cancer cell proliferation, specifically by determining the effect of genistein on ER-related cell signaling molecules involved in cell proliferation, cell survival and apoptosis. Based on literature reports, the ER-related cell signaling molecules chosen for this study were ERK1/2, p90RSK, JNK, Akt and NFκB. ERK1/2 and, p90RSK are involved in cell proliferation; JNK, Akt and NFκB are involved in cell survival and/or apoptosis.&#x2028; Methods: The effect of genistein at 1 µM (low concentration) and 100 µM (high concentration) on cell signaling molecules was determined by a BioPlex Phosphoprotein detection kit. Results obtained from the BioPlex assay were confirmed by immunodetection. Cell proliferation was determined at 24, 48, and 72 hrs by the MTT (3-[4,5- dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium) assay. This study was carried out in T47D (ERα and ERβ) and MDA-MB-231 (ERβ) breast cancer cells.&#x2028; Results: At 100 µM genistein exposure we observed a decrease in phosphorylated p90RSK (40%) in T47D cells and an increase in phosphorylated JNK (45%) in MDA-MB-231 cells in a statistically significant (p&lt;0.05) manner. At 100 µM genistein exposure, a statistically significant (p&lt;0.001) decrease in cell proliferation was observed in T47D cells (20-40%) and MDA-MB-231 cells (30-60%) as compared to the control. At 1 µM genistein exposure, there was a statistically significant (p&lt;0.05) decrease (15%) of phosphorylated JNK in MDA-MB-231 cells. MDA-MB-231 cells exposed to 1 µM genistein did not show any statistically significant difference in cell proliferation as compared to the control. T47D cells exposed to 1 µM of genistein for 24 – 72 hours showed a statistically significant (p&lt;0.001) increase (25 to 70%) in cell proliferation.&#x2028; Conclusions: Our data suggests that in T47D cells which have both ERs, decreased cell proliferation due to high concentrations of genistein is probably due to a decrease in phosphorylated p90RSK, an ER-related cell proliferation protein. In MDA-MB-231 cells with only ERβ, the decrease in cell proliferation is probably due to an increase in phosphorylated JNK, an apoptotic protein. Our results suggest that at high concentrations of genistein, the cellular pathways of inhibition of breast cancer cell proliferation likely depend on ER status. This study reveals the importance of genistein as an effective chemotherapeutic agent in breast cancers that contain both ERs and only ERβ.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6019.