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Nat Commun. 2014 Oct 3;5:5073. doi: 10.1038/ncomms6073.

Diurnal suppression of EGFR signalling by glucocorticoids and implications for tumour progression and treatment.

Author information

1
1] Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel [2] Unit of Histology, Embryology and Applied Biology, Department of Experimental, Diagnostic and Specialty Medicine, Bologna University, Bologna 40138, Italy.
2
Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
3
Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot 76100, Israel.
4
Division of Molecular Genome Analysis, German Cancer Research Centre (DKFZ), 69120 Heidelberg, Germany.
5
Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel.
6
Unit of Histology, Embryology and Applied Biology, Department of Experimental, Diagnostic and Specialty Medicine, Bologna University, Bologna 40138, Italy.
7
1] Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada M5S 1A8 [2] Department of Pathology, University Health Network, Toronto, Ontario, Canada M5G 2C4 [3] IPATIMUP, University of Porto, Porto 4200-465, Portugal.

Abstract

Signal transduction by receptor tyrosine kinases (RTKs) and nuclear receptors for steroid hormones is essential for body homeostasis, but the cross-talk between these receptor families is poorly understood. We observed that glucocorticoids inhibit signalling downstream of EGFR, an RTK. The underlying mechanism entails suppression of EGFR's positive feedback loops and simultaneous triggering of negative feedback loops that normally restrain EGFR. Our studies in mice reveal that the regulation of EGFR's feedback loops by glucocorticoids translates to circadian control of EGFR signalling: EGFR signals are suppressed by high glucocorticoids during the active phase (night-time in rodents), while EGFR signals are enhanced during the resting phase. Consistent with this pattern, treatment of animals bearing EGFR-driven tumours with a specific kinase inhibitor was more effective if administered during the resting phase of the day, when glucocorticoids are low. These findings support a circadian clock-based paradigm in cancer therapy.

PMID:
25278152
PMCID:
PMC4205848
DOI:
10.1038/ncomms6073
[Indexed for MEDLINE]
Free PMC Article

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