TCDD mediates inhibition of p53 and activation of ERα signaling in MCF-7 cells at moderate hypoxic conditions

  • Authors:
    • Anja Seifert
    • Helge Taubert
    • Sabine Hombach-Klonisch
    • Bernd Fischer
    • Anne Navarrete Santos
  • View Affiliations

  • Published online on: August 1, 2009     https://doi.org/10.3892/ijo_00000354
  • Pages: 417-424
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Abstract

TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) is known to promote cancer initiation and progression and accumulates in mammary fat tissue. Effects of TCDD are mediated by the aryl hydrocarbon receptor (AhR). Physiological conditions of moderate hypoxia in breast cancer also activate another transcription factor, hypoxia-inducible factor-1 alpha (HIF-1α). In addition, the transcription factors p53 and the estrogen receptor alpha (ERα) are important key players in breast cancer progression. Here, human breast cancer cells cultured under mild hypoxic conditions were exposed to TCDD and analyzed for regulation of p53 signaling and ERα transactivation. Simultaneous exposure to TCDD and hypoxia resulted in a moderate but reproducible inhibition of p53 expression. Both the direct activation of the ERα and the transcriptional regulation of Hdm2 mediated this inhibition. As consequence the p53-mediated target gene expression (Dusp5) was reduced. Silencing of Dusp5 by simultaneous exposure of TCDD and hypoxia or by RNAi led to increased phosphorylation of ERK1/2. This increase resulted in transactivation of ERα and induction of ERα-mediated transcription of Hdm2 and SOCS3. Specificity of ERα-transactivation by ERK1/2 was confirmed by treatment with MAPKK-inhibitor PD98059. The combination of inhibition of functional p53 protein and induction of ERα signaling could serve as a model for the operational sequence of TCDD effects to prevent cell death and promote breast tumor progression.

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August 2009
Volume 35 Issue 2

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Seifert A, Taubert H, Hombach-Klonisch S, Fischer B and Navarrete Santos A: TCDD mediates inhibition of p53 and activation of ERα signaling in MCF-7 cells at moderate hypoxic conditions. Int J Oncol 35: 417-424, 2009.
APA
Seifert, A., Taubert, H., Hombach-Klonisch, S., Fischer, B., & Navarrete Santos, A. (2009). TCDD mediates inhibition of p53 and activation of ERα signaling in MCF-7 cells at moderate hypoxic conditions. International Journal of Oncology, 35, 417-424. https://doi.org/10.3892/ijo_00000354
MLA
Seifert, A., Taubert, H., Hombach-Klonisch, S., Fischer, B., Navarrete Santos, A."TCDD mediates inhibition of p53 and activation of ERα signaling in MCF-7 cells at moderate hypoxic conditions". International Journal of Oncology 35.2 (2009): 417-424.
Chicago
Seifert, A., Taubert, H., Hombach-Klonisch, S., Fischer, B., Navarrete Santos, A."TCDD mediates inhibition of p53 and activation of ERα signaling in MCF-7 cells at moderate hypoxic conditions". International Journal of Oncology 35, no. 2 (2009): 417-424. https://doi.org/10.3892/ijo_00000354