Background: Our previous results were the first to show that physiological concentrations (1 μM) of genistein, a soy component, in the presence of17β-estradiol (1 nM) inhibited the cell proliferation of MDA-MB-231 (Estrogen receptor (ER) β positive) breast cancer cells. These results are relevant in premenopausal women with breast cancer of the ERα-negative and ERβ-positive type, especially given the increasing trends of soy intake among the US population in the past decade. The aim of the present study was to identify the mechanism by which genistein plus 17β-estradiol inhibits the cell proliferation of ERα-negative and ERb-positive breast cancer cells. Our hypothesis is that the balance of signaling actions by genistein plus 17β-estradiol from different signaling pathways is likely to lead to the cell's choice to either proliferate or enter the apoptotic pathway. For this purpose, the effect of low and high concentrations of genistein (1 μM and 100 μM) in the presence or absence of 17β-estradiol (1 nM) was studied on the expression of cell signaling proteins involved in cell proliferation, survival and apoptosis (pERK1/2, pAkt, Bax and Bcl2) and correlated to cell proliferation and apoptosis in MDA-MB-231 (ERβ positive and ERα negative) breast cancer cells. Methods: Cell proliferation was determined by the MTT assay, apoptosis determined microscopically by the use of acridine orange and ethidium bromide dyes and the expression of cell signaling proteins by western blotting. Results: Our results show that 1μM genistein plus 17β-estradiol significantly increased apoptosis (p<0.05) as compared to the control (12.47% vs 5.87% respectively). Increased expression of Bax/Bcl2 (2.5 fold) along with a decreased expression of phosphorylated ERK1/2 (2 fold) was observed in cells treated with 1μM genistein plus 17β-estradiol as compared to the control cells. Phosphorylated Akt did not show any differences in the treatment condition as compared to the control. High concentrations of genistein (100 μM) in the presence or absence of 17β-estradiol also increased apoptosis; however these changes could not be correlated to the expression of Bax/Bcl2, or pERK1/2. Conclusion: In conclusion, our results show that physiological concentrations of genistein in the presence of17β-estradiol inhibit cell growth through apoptosis via increased Bax/Bcl2 and a concomitant decrease in pERK1/2 expression. Our results also suggest that different concentrations of genistein elicit cell responses through different signaling mechanisms. These results are especially relevant to the cohort of premenopausal women with breast cancer of the ERβ positive and ERα negative type. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-04-07.
#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.
 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.
 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<0.05) manner. At 100 µM genistein exposure, a statistically significant (p<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<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<0.001) increase (25 to 70%) in cell proliferation.
 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.
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