This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Vijayanathan, V. Articles by Thomas, T. Search for Related Content PubMed PubMed Citation Articles by Vijayanathan, V. Articles by Thomas, T.

Physiologic Levels of 2-Methoxyestradiol Interfere with Nongenomic Signaling of 17ß-Estradiol in Human Breast Cancer Cells

Authors' Affiliations: Departments of ¹ Medicine and ² Environmental and Occupational Medicine, Environmental and Occupational Health Sciences Institute and The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey, and ³ Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina

Requests for reprints: Thresia Thomas, Department of Environmental and Occupational Medicine, 125 Paterson Street, Clinical Academic Building, Room 7092, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, NJ 08903. Phone: 732-235-8458; Fax: 732-235-8473; E-mail: thomasth{at}umdnj.edu.

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 ER-positive breast cancer cells, we studied the effects of 2ME on cell proliferation and cell signaling. Our hypothesis is that 17ß-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 ER in response to E₂ in MCF-7 and T-47D 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 ER level by 72 hours. Accelerated down-regulation of ER 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.

This article has been cited by other articles:

				S. A. Salama, A. B. Nasr, R. K. Dubey, and A. Al-Hendy Estrogen Metabolite 2-Methoxyestradiol Induces Apoptosis and Inhibits Cell Proliferation and Collagen Production in Rat and Human Leiomyoma Cells: A Potential Medicinal Treatment for Uterine Fibroids Reproductive Sciences, December 1, 2006; 13(8): 542 - 550. [Abstract] [PDF]