title: Diurnal suppression of EGFR signalling by glucocorticoids and implications for tumour progression and treatment.
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.
authors.affiliation: 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.
authors.forename: Mattia
authors.initials: M
authors.lastname: Lauriola
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Yehoshua
authors.initials: Y
authors.lastname: Enuka
authors.affiliation: Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Amit
authors.initials: A
authors.lastname: Zeisel
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Gabriele
authors.initials: G
authors.lastname: D'Uva
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Lee
authors.initials: L
authors.lastname: Roth
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Sharon-Sevilla
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Moshit
authors.initials: M
authors.lastname: Lindzen
authors.affiliation: Division of Molecular Genome Analysis, German Cancer Research Centre (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Kirti
authors.initials: K
authors.lastname: Sharma
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Nava
authors.initials: N
authors.lastname: Nevo
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Morris
authors.initials: M
authors.lastname: Feldman
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Silvia
authors.initials: S
authors.lastname: Carvalho
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Hadas
authors.initials: H
authors.lastname: Cohen-Dvashi
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Merav
authors.initials: M
authors.lastname: Kedmi
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Nir
authors.initials: N
authors.lastname: Ben-Chetrit
authors.affiliation: Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Alon
authors.initials: A
authors.lastname: Chen
authors.affiliation: Unit of Histology, Embryology and Applied Biology, Department of Experimental, Diagnostic and Specialty Medicine, Bologna University, Bologna 40138, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: Solmi
authors.affiliation: Division of Molecular Genome Analysis, German Cancer Research Centre (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Wiemann
authors.affiliation: 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.
authors.forename: Fernando
authors.initials: F
authors.lastname: Schmitt
authors.affiliation: Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Eytan
authors.initials: E
authors.lastname: Domany
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Yosef
authors.initials: Y
authors.lastname: Yarden
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D002940:Circadian Rhythm; D018450:Disease Progression; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D005938:Glucocorticoids / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000473:pathology*; D009991:Oscillometry; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D015398:Signal Transduction; D016896:Treatment Outcome
chemical_list: D005938:Glucocorticoids; D008024:Ligands; D011965:Receptors, Glucocorticoid; D066246:ErbB Receptors