TY - JOUR
T1 - Physiologic levels of 2-methoxyestradiol interfere with nongenomic signaling of 17β-estradiol in human breast cancer cells
AU - Vijayanathan, Veena
AU - Venkiteswaran, Sripriya
AU - Nair, Sandhya K.
AU - Verma, Arti
AU - Thomas, T. J.
AU - Bao, Ting Zhu
AU - Thomas, Thresia
PY - 2006/4/1
Y1 - 2006/4/1
N2 - Purpose: The purpose of this investigation is to determine the effects of physiologic levels (10-50 nmol/L) of 2-methoxyestradiol (2ME) on the growth of estrogen receptor (ER) - positive breast cancer cells and provide insights into its mechanism(s) of action. Experimental Design: Using the ERα-positive breast cancer cells, we studied the effects of 2ME on cell proliferation and cell signaling. Our hypothesis is that 17β-estradiol (E2) and 2ME can affect shared cell signaling pathways, leading to different outcomes in cell proliferation, depending on the absence/presence of E2. Results: E2 stimulated the growth of MCF-7 and T-47 D cells and induced Akt phosphorylation, a nongenomic signaling pathway. In the absence of E2, 10 to 50 nmol/L of 2ME enhanced cell growth and Akt phosphorylation. However, in the presence of E2, 2ME inhibited E2-induced cell growth and prevented E2-induced Akt phosphorylation. Confocal microscopic studies showed that 2ME inhibited subcellular distribution of ERα in response to E2 in MCF-7 and T-47 D cells. 2ME also down-regulated E2-induced increases in cyclic AMP and ornithine decarboxylase activity. In addition, treatment of MCF-7 cells with 2ME in the presence of E2 resulted in a decrease in ERα level by 72 hours. Accelerated down-regulation of ERα may contribute to growth inhibition in the presence of E2/2ME combinations. In contrast, a concentration of up to 2.5 μmol/L 2ME had no effect on the growth of ER-negative SK-BR-3 cells, either in the presence or absence of E2. Conclusions: Our results provide evidence for the nongenomic action of 2ME in ER-positive cells. In the presence of E2, 2ME suppressed E2-induced cell growth. Akt signaling, and generation of cyclic AMP, whereas it acted as an estrogen in the absence of E2. The intriguing growth-stimulatory and growth-inhibitory effects of 2ME on breast cancer cells suggests the need for its selective use in patients.
AB - Purpose: The purpose of this investigation is to determine the effects of physiologic levels (10-50 nmol/L) of 2-methoxyestradiol (2ME) on the growth of estrogen receptor (ER) - positive breast cancer cells and provide insights into its mechanism(s) of action. Experimental Design: Using the ERα-positive breast cancer cells, we studied the effects of 2ME on cell proliferation and cell signaling. Our hypothesis is that 17β-estradiol (E2) and 2ME can affect shared cell signaling pathways, leading to different outcomes in cell proliferation, depending on the absence/presence of E2. Results: E2 stimulated the growth of MCF-7 and T-47 D cells and induced Akt phosphorylation, a nongenomic signaling pathway. In the absence of E2, 10 to 50 nmol/L of 2ME enhanced cell growth and Akt phosphorylation. However, in the presence of E2, 2ME inhibited E2-induced cell growth and prevented E2-induced Akt phosphorylation. Confocal microscopic studies showed that 2ME inhibited subcellular distribution of ERα in response to E2 in MCF-7 and T-47 D cells. 2ME also down-regulated E2-induced increases in cyclic AMP and ornithine decarboxylase activity. In addition, treatment of MCF-7 cells with 2ME in the presence of E2 resulted in a decrease in ERα level by 72 hours. Accelerated down-regulation of ERα may contribute to growth inhibition in the presence of E2/2ME combinations. In contrast, a concentration of up to 2.5 μmol/L 2ME had no effect on the growth of ER-negative SK-BR-3 cells, either in the presence or absence of E2. Conclusions: Our results provide evidence for the nongenomic action of 2ME in ER-positive cells. In the presence of E2, 2ME suppressed E2-induced cell growth. Akt signaling, and generation of cyclic AMP, whereas it acted as an estrogen in the absence of E2. The intriguing growth-stimulatory and growth-inhibitory effects of 2ME on breast cancer cells suggests the need for its selective use in patients.
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U2 - 10.1158/1078-0432.CCR-05-2172
DO - 10.1158/1078-0432.CCR-05-2172
M3 - Article
C2 - 16609013
AN - SCOPUS:33646239176
SN - 1078-0432
VL - 12
SP - 2038
EP - 2048
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 7 I
ER -
