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

Veena Vijayanathan, Sripriya Venkiteswaran, Sandhya K. Nair, Arti Verma, T. J. Thomas, Ting Zhu Bao, Thresia Thomas

Research output: Contribution to journalArticle

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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 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.

Original languageEnglish (US)
Pages (from-to)2038-2048
Number of pages11
JournalClinical Cancer Research
Volume12
Issue number7 I
DOIs
StatePublished - Apr 1 2006

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Estradiol
Breast Neoplasms
Estrogen Receptors
Growth
Somatostatin-Secreting Cells
Phosphorylation
Cyclic AMP
2-methoxyestradiol
Cell Proliferation
Ornithine Decarboxylase
MCF-7 Cells
Estrogens
Research Design
Down-Regulation

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Vijayanathan, Veena ; Venkiteswaran, Sripriya ; Nair, Sandhya K. ; Verma, Arti ; Thomas, T. J. ; Bao, Ting Zhu ; Thomas, Thresia. / Physiologic levels of 2-methoxyestradiol interfere with nongenomic signaling of 17β-estradiol in human breast cancer cells. In: Clinical Cancer Research. 2006 ; Vol. 12, No. 7 I. pp. 2038-2048.
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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 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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Physiologic levels of 2-methoxyestradiol interfere with nongenomic signaling of 17β-estradiol in human breast cancer cells. / Vijayanathan, Veena; Venkiteswaran, Sripriya; Nair, Sandhya K.; Verma, Arti; Thomas, T. J.; Bao, Ting Zhu; Thomas, Thresia.

In: Clinical Cancer Research, Vol. 12, No. 7 I, 01.04.2006, p. 2038-2048.

Research output: Contribution to journalArticle

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

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