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Abstract:
Cushing's disease (CD) arises from pituitary-dependent glucocorticoid
excess due to an ACTH-secreting corticotroph tumor. Genetic hits in
oncogenes and tumor suppressor genes that afflict other pituitary tumor
subtypes are not found in corticotrophinomas. Recently, a somatic
mutational hotspot was found in up to half of corticotrophinomas in the
USP8 gene that encodes a protein that impairs the downregulation of the
epidermal growth factor receptor (EGFR) and enables its constitutive
signaling. EGF is an important regulator of corticotroph function and
its receptor is highly expressed in Cushing's pituitary tumors, where it
leads to increased ACTH synthesis in vitro and in vivo. The mutational
hotspot found in corticotrophinomas hyper-activates USP8, enabling it to
rescue EGFR from lysosomal degradation and ensure its stimulatory
signaling. This review presents new developments in the study of the
genetics of CD and focuses on the USP8-EGFR system as trigger and target
of corticotroph tumorigenesis.
