TCDD mediates inhibition of p53 and activation of ERalpha signaling in MCF-7 cells at moderate hypoxic conditions.
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-1alpha). In addition, the transcription factors p53 and the estrogen receptor alpha (ERalpha) 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 ERalpha transactivation. Simultaneous exposure to TCDD and hypoxia resulted in a moderate but reproducible inhibition of p53 expression. Both the direct activation of the ERalpha 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 ERalpha and induction of ERalpha-mediated transcription of Hdm2 and SOCS3. Specificity of ERalpha-transactivation by ERK1/2 was confirmed by treatment with MAPKK-inhibitor PD98059. The combination of inhibition of functional p53 protein and induction of ERalpha signaling could serve as a model for the operational sequence of TCDD effects to prevent cell death and promote breast tumor progression.
Seifert
Anja
A
Department of Pharmacology, Otto-von-Guericke University, D-39120 Magdeburg, Germany. seifert-anja-halle@gmx.de
Taubert
Helge
H
Hombach-Klonisch
Sabine
S
Fischer
Bernd
B
Navarrete Santos
Anne
A
D001943:Breast Neoplasms / Q000473:pathology*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D054637:Dual-Specificity Phosphatases / Q000037:antagonists & inhibitors; D047628:Estrogen Receptor alpha / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D010766:Phosphorylation; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*
C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D000072317:Polychlorinated Dibenzodioxins; D016159:Tumor Suppressor Protein p53; D048049:Extracellular Signal-Regulated MAP Kinases; C442320:DUSP5 protein, human; D054637:Dual-Specificity Phosphatases