The epidermal growth factor receptor (EGFR), expressed in adrenocorticotrophic hormone (ACTH)-secreting pituitary adenomas causing Cushing disease, regulates ACTH production and corticotroph proliferation. To elucidate the utility of EGFR as a therapeutic target for Cushing disease, we generated transgenic (Tg) mice with corticotroph-specific human EGFR expression (corti-EGFR-Tg) using a newly constructed corticotroph-specific promoter. Pituitary-specific EGFR expression was observed by 2.5 months, and aggressive ACTH-secreting pituitary adenomas with features of Crooke's cells developed by 8 months with 65% penetrance observed. Features consistent with the Cushing phenotype included elevated plasma ACTH and corticosterone levels, increased body weight, glucose intolerance, and enlarged adrenal cortex. Gefitinib, an EGFR tyrosine kinase inhibitor, suppressed tumor POMC expression and downstream EGFR tumor signaling, and ACTH and corticosterone levels were attenuated by 80% and 78%, respectively. Both E2F1 and phosphorylated Ser-337 E2F1 were increased in corti-EGFR-Tg mice and also colocalized with human POMC (hPOMC) in human pituitary corticotroph tumor samples. EGFR inhibition reversed E2F1 activity in vivo, whereas E2F1 inhibition suppressed POMC and ACTH in cultured human pituitary tumor cells. The corti-EGFR-Tg phenotype recapitulates ACTH-secreting pituitary adenomas and Cushing disease, validating the relevance of EGFR to corticotroph tumorigenesis. E2F1 is identified as a promising corticotroph-specific target for ACTH-dependent Cushing disease.
Pubmed ID: 29264472 RIS Download
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View all literature mentionsThis polyclonal targets POMC
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View all literature mentionsThis monoclonal targets Phospho-Akt (Ser473)
View all literature mentionsThis monoclonal targets p44/42 MAPK (Erk1/2)
View all literature mentionsThis polyclonal targets Erk1/2
View all literature mentionsThis monoclonal targets ACTH
View all literature mentionsThis polyclonal targets E2F1 S337
View all literature mentionsThis polyclonal targets EGFR.
View all literature mentionsThis polyclonal targets PRL
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View all literature mentionsThis polyclonal targets POMC
View all literature mentionsThis monoclonal targets EGF Receptor
View all literature mentionsThis monoclonal targets Actin
View all literature mentionsThis monoclonal targets Glucocorticoid Receptor
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View all literature mentionsThis polyclonal targets DRD2
View all literature mentionsThis polyclonal targets E2F1 S337
View all literature mentionsThis monoclonal targets Rb binding domain of E2F-1 p60 protein of human origin
View all literature mentionsThis polyclonal targets Phospho-EGF Receptor (Tyr1068)
View all literature mentionsThis monoclonal targets Akt2
View all literature mentionsThis monoclonal targets Phospho-Akt (Ser473)
View all literature mentionsThis monoclonal targets p44/42 MAPK (Erk1/2)
View all literature mentionsThis polyclonal targets Erk1/2
View all literature mentionsThis monoclonal targets ACTH
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