Physiologic levels of 2-methoxyestradiol interfere with nongenomic signaling of 17beta-estradiol in human breast cancer cells.

Abstract

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 ERalpha-positive breast cancer cells, we studied the effects of 2ME on cell proliferation and cell signaling. Our hypothesis is that 17beta-estradiol (E(2)) and 2ME can affect shared cell signaling pathways, leading to different outcomes in cell proliferation, depending on the absence/presence of E(2).

RESULTS:

E(2) stimulated the growth of MCF-7 and T-47 D cells and induced Akt phosphorylation, a nongenomic signaling pathway. In the absence of E(2), 10 to 50 nmol/L of 2ME enhanced cell growth and Akt phosphorylation. However, in the presence of E(2), 2ME inhibited E(2)-induced cell growth and prevented E(2)-induced Akt phosphorylation. Confocal microscopic studies showed that 2ME inhibited subcellular distribution of ERalpha in response to E(2) in MCF-7 and T-47D cells. 2ME also down-regulated E(2)-induced increases in cyclic AMP and ornithine decarboxylase activity. In addition, treatment of MCF-7 cells with 2ME in the presence of E(2) resulted in a decrease in ERalpha level by 72 hours. Accelerated down-regulation of ERalpha may contribute to growth inhibition in the presence of E(2)/2ME combinations. In contrast, a concentration of up to 2.5 mumol/L 2ME had no effect on the growth of ER-negative SK-BR-3 cells, either in the presence or absence of E(2).

CONCLUSIONS:

Our results provide evidence for the nongenomic action of 2ME in ER-positive cells. In the presence of E(2), 2ME suppressed E(2)-induced cell growth, Akt signaling, and generation of cyclic AMP, whereas it acted as an estrogen in the absence of E(2). The intriguing growth-stimulatory and growth-inhibitory effects of 2ME on breast cancer cells suggests the need for its selective use in patients.

• Authors: Veena Vijayanathan, Sripriya Venkiteswaran, Sandhya K Nair, Arti Verma, T J Thomas, Bao Ting Zhu, Thresia Thomas
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 12 Issue 7 Pt 1 Pg. 2038-48 (Apr 01 2006) ISSN: 1078-0432 [Print] United States
• PMID: 16609013 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Estrogen Receptor alpha
• Polyamines
• Estradiol
• 2-Methoxyestradiol
• Cyclic AMP

Topics

• 2-Methoxyestradiol
• Breast Neoplasms (drug therapy, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cyclic AMP (biosynthesis)
• Dose-Response Relationship, Drug
• Estradiol (analogs & derivatives, pharmacology)
• Estrogen Receptor alpha (drug effects)
• Female
• Humans
• Phosphorylation
• Polyamines (metabolism)
• Signal Transduction (drug effects)
• Structure-Activity Relationship
• Time Factors
• Tumor Cells, Cultured