2-methoxyestradiol is an estrogen receptor agonist that supports tumor growth in murine xenograft models of breast cancer

Tara E Sutherland, Michael Schuliga, Trudi Harris, Bedrich L Eckhardt, Robin L Anderson, Lilly Quan, Alastair G Stewart

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46 Citations (Scopus)

Abstract

PURPOSE: 2-Methoxyestradiol (2MEO) is being developed as a novel antitumor agent based on its antiangiogenic activity, tumor cell cytotoxicity, and apparent lack of toxicity. However, pharmacologic concentrations of 2MEO bind to estrogen receptors (ER). We have therefore examined the ER activity of 2MEO.EXPERIMENTAL DESIGN: Estrogenic actions of 2MEO were evaluated by changes in gene expression of the ER-positive (MCF7) breast tumor cell line and, in vivo, estrogenicity was assessed in breast tumor xenograft models and by measuring endocrine responses in uterus and liver.RESULTS: In the ER-positive breast tumor cell line (MCF7), microarray experiments revealed that 269 of 279 changes in gene expression common to 2MEO and estradiol were prevented by the ER antagonist, ICI 182,780. Changes in the expression of selected genes and their sensitivity to inhibition by ICI 182,780 were confirmed by quantitative reverse transcription-PCR measurement. Activation of ER in MCF7 cells by 2MEO was further confirmed by stimulation of an estrogen response element-dependent reporter gene that was blocked by ICI 182,780 (1 micromol/L). Doses of 2MEO (15-150 mg/kg) that had no antitumor efficacy in either nu/nu BALB/c or severe combined immunodeficient mice bearing ER-negative MDA-MB-435 tumors had uterotropic and hepatic estrogen-like actions. In female nu/nu BALB/c mice inoculated with the estrogen-dependent MCF7 tumor cells, 2MEO (50 mg/kg/d) supported tumor growth.CONCLUSIONS: Tumor growth enhancement by 2MEO at doses generating serum levels (100-500 nmol/L) that have estrogenic activity suggests that a conservative approach to the further clinical evaluation of this agent should be adopted and that its evaluation in breast cancer is inappropriate.
Original languageEnglish
Pages (from-to)1722-1732
JournalClinical Cancer Research
Volume11
Issue number5
DOIs
Publication statusPublished - 1 Mar 2005

Bibliographical note

Acknowledgments
We thank Associate Professor Susan Charman, Victorian College of Pharmacy, Monash University, for advice regarding the preparation of 2MEO for in vivo studies and the staff of the Peter Mac Microarray Facility for providing the arrays and for expert advice.

Keywords

  • Animals
  • Breast Neoplasms
  • Cell Proliferation
  • Disease Models
  • Animal
  • Estradiol
  • Female
  • Gene Expression Profiling
  • Humans
  • Mice
  • Inbred BALB C
  • Oligonucleotide Array Sequence Analysis
  • Receptors
  • Estrogen
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transplantation
  • Heterologous
  • Tumor Cells
  • Cultured

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