Abstract
Cell cycle proteins are critical to pituitary development, but their contribution to lineage-specific tumorigenesis has not been well-elucidated. Emerging evidence from in vitro human tumor analysis and transgenic mouse models indicates that G1/S-related cell cycle proteins, particularly cyclin E, p27, Rb, and E2F1, drive molecular mechanisms that underlie corticotroph-specific differentiation and development of Cushing disease. The aim of this review is to summarize the literature and discuss the complex role of cell cycle regulation in Cushing disease, with a focus on identifying potential targets for therapeutic intervention in patients with these tumors.
Highlights
Pituitary corticotrophs play critical physiologic roles in hypothalamic–pituitary–adrenal axis functions, including the acute stress response, regulation of body metabolism and energy expenditures, and immune function [1]
Patients with Cushing disease caused by a pituitary corticotroph adenoma can manifest obesity, diabetes, susceptibility to infections, psychosis, and coagulopathy, which contributes to increased mortality [2]
By co-staining with human pituitary hormones, we found that E2F1 co-localizes with POMC in normal human corticotrophs, but not with prolactin or growth hormone in lactotrophs or somatotrophs, respectively [59]
Summary
Pituitary corticotrophs play critical physiologic roles in hypothalamic–pituitary–adrenal axis functions, including the acute stress response, regulation of body metabolism and energy expenditures, and immune function [1]. Patients with Cushing disease caused by a pituitary corticotroph adenoma can manifest obesity, diabetes, susceptibility to infections, psychosis, and coagulopathy, which contributes to increased mortality [2]. Surgical tumor resection is the primary therapy for Cushing disease, but persistent/recurrent disease is seen in 12–40% of patients depending on surgical expertise, the definition of remission, and the duration of follow-up [3, 4]. Pituitary-directed radiation and bilateral adrenalectomy to inhibit adrenal cortisol production are effective at inducing biochemical control but are infrequently used. Lifelong replacement glucocorticoid and mineralocorticoid is needed, and the loss of negative feedback on pituitary adrenocorticotropic hormone (ACTH) can lead to tumor growth [5, 6]
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