2-Methoxyestradiol inhibits progesterone-dependent tissue factor expression and activity in breast cancer cells

Marisol Quezada, Jorge Diaz, Soledad Henriquez, Maria Loreto Bravo, Evelyn Aranda, Barbara Oliva, Manuel Villalon, Sumie Kato, Mauricio A. Cuello, Jan J. Brosens, Carol A. Lange, Gareth I. Owen

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

2-Methoxyestradiol (2ME) is an endogenous metabolite of 17β-estradiol with antiangiogenic and antitumor properties, although its mechanisms of action remain unclear. Progestins in hormone replacement therapy increase the risk of breast cancer. Progesterone also enhances the procoagulant activity and invasive potential of progesterone receptor (PR)-positive breast cancer cell lines, an effect largely mediated by induction of tissue factor (TF), the cellular activator of the coagulation cascade. Here we show that 2ME abrogates the induction TF expression in progesterone-treated breast cancer cells via a mechanism that does not involve the estrogen receptor. Instead, we demonstrate that by selectively antagonizing ERK1/2 signaling in breast cancer cells, 2ME limits the transactivation potential of ligand-bound PR and inhibits the expression of endogenous progesterone targets, such as TF and signal transducer and activator of transcription 5. We further demonstrate that 2ME can alter the phosphorylation status of PR. Thus, 2ME prevents progesterone-dependent increase in breast cancer cell invasiveness and procoagulant activity by uncoupling PR from the ERK1/2 signal transduction pathway.

Original languageEnglish (US)
Pages (from-to)117-126
Number of pages10
JournalHormones and Cancer
Volume1
Issue number3
DOIs
StatePublished - 2010

Bibliographical note

Funding Information:
Acknowledgements We wish to thank Dr. Kathryn Horwitz, UCHSC (CO, USA), for originally supplying the T47D breast cancer cell lines. We also acknowledge our funding from the Chilean ministry of education, FONDECYT grant 1060495 and FONDEF D06I1017. We further acknowledge the support from the NIHR Biomedical Research Centre funding scheme to JJB.

Keywords

  • 2-Methoxyestradiol
  • Breast cancer
  • Progesterone receptor
  • STAT5
  • Tissue factor

Fingerprint

Dive into the research topics of '2-Methoxyestradiol inhibits progesterone-dependent tissue factor expression and activity in breast cancer cells'. Together they form a unique fingerprint.

Cite this