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ERK1/2 inhibition increases antiestrogen treatment efficacy by interfering with hypoxia-induced downregulation of ERalpha: a combination therapy potentially targeting hypoxic and dormant tumor cells.

Author:
  • Åsa Kronblad
  • Ingrid Hedenfalk
  • Elise Nilsson
  • Sven Påhlman
  • Göran Landberg
Publishing year: 2005
Language: English
Pages: 6835-6841
Publication/Series: Oncogene
Volume: 24
Issue: 45
Document type: Journal article
Publisher: Nature Publishing Group

Abstract english

Tumor hypoxia is associated with cancer invasiveness, metastasis and treatment failure. Recent data suggest that the major target for endocrine treatment in breast cancer, ER alpha, is downregulated during hypoxia, but the mechanism behind this remains unknown. MAPK signaling as well as ER alpha regulation has earlier been independently linked to hypoxia and we now demonstrate HIF-1 alpha and ERK1/2-activation in vivo towards the necrotic zone in DCIS of the breast, parallel with ER alpha downregulation. Hypoxia further caused transcriptional downregulation of ER alpha via activation of ERK1/2 in cell lines and, importantly, MEK1/2 inhibitors (U0126 or PD184352) or ERK1/2 suppression by siRNA partially restored the ERa expression. U0126 combined with tamoxifen accordingly produced an increased efficacy of the anti-estrogens during hypoxia. Base don these findings, we suggest a promising novel therapy for ER alpha-positive breast cancer where a combination of endocrine treatment and ERK1/2 inhibitors may increase treatment response by improved targeting of dormant hypoxic tumor cells.

Keywords

  • Cancer and Oncology
  • hypoxia
  • MAPK
  • breast cancer
  • ERK1/2
  • tamoxifen
  • ER alpha

Other

Published
  • Pathology, Malmö
  • ISSN: 1476-5594
Sven Påhlman
E-mail: sven [dot] pahlman [at] med [dot] lu [dot] se

Professor

Division of Translational Cancer Research

+46 46 222 64 21

MV406 312K1

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