Cooperation between Cyclin E and p27Kip1 in Pituitary Tumorigenesis

Roussel-Gervais, Audrey; Bilodeau, Steve; Vallette, Sophie; Lacroix, André; Figarella‐Branger, Dominique; Brue, Thierry; Drouin, Jacques

doi:10.1210/me.2010-0091

Cited by 80 publications

(67 citation statements)

References 49 publications

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“…EGFR-expressing corticotrophinomas also had very weak or absent immunoreactivity for the cell cycle inhibitor p27 (41). This is of interest, since loss of p27 protein (but not transcript) is a prominent feature of human corticotrophinomas (53,54). One hypothesis is that activated EGFR triggers signaling cascades that downregulate p27 in corticotrophinomas, which in addition to the stimulatory action on ACTH synthesis contributes to their tumorigenesis.…”

Section: Egfr and Corticotroph Functionmentioning

confidence: 99%

Decoding the genetic basis of Cushing's disease: USP8 in the spotlight

Theodoropoulou

Reincke

Faßnacht

et al. 2015

European Journal of Endocrinology

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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.

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Section: Egfr and Corticotroph Functionmentioning

confidence: 99%

Decoding the genetic basis of Cushing's disease: USP8 in the spotlight

Theodoropoulou

Reincke

Faßnacht

et al. 2015

European Journal of Endocrinology

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“…In pituitary corticotroph tumors expressing EGFR, p27 Kip1 , a cyclin-dependent kinase inhibitor, is downregulated (18). Mice with disrupted p27 also develop pituitary tumors mostly expressing proopiomelanocortin (POMC), a precursor protein of ACTH (19)(20)(21)(22). We hypothesized that the receptor could be a novel target for therapy of Cushing disease, and therefore tested EGFR signaling in ACTH-secreting pituitary adenomas.…”

Section: Introductionmentioning

confidence: 99%

EGFR as a therapeutic target for human, canine, and mouse ACTH-secreting pituitary adenomas

Fukuoka

Cooper²,

Ben-Shlomo³

et al. 2011

J. Clin. Invest.

235

169

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Cushing disease is a condition in which the pituitary gland releases excessive adrenocorticotropic hormone (ACTH) as a result of an adenoma arising from the ACTH-secreting cells in the anterior pituitary. ACTH-secreting pituitary adenomas lead to hypercortisolemia and cause significant morbidity and mortality. Pituitarydirected medications are mostly ineffective, and new treatment options are needed. As these tumors express EGFR, we tested whether EGFR might provide a therapeutic target for Cushing disease. Here, we show that in surgically resected human and canine corticotroph cultured tumors, blocking EGFR suppressed expression of proopiomelanocortin (POMC), the ACTH precursor. In mouse corticotroph EGFR transfectants, ACTH secretion was enhanced, and EGF increased Pomc promoter activity, an effect that was dependent on MAPK. Blocking EGFR activity with gefitinib, an EGFR tyrosine kinase inhibitor, attenuated Pomc expression, inhibited corticotroph tumor cell proliferation, and induced apoptosis. As predominantly nuclear EGFR expression was observed in canine and human corticotroph tumors, we preferentially targeted EGFR to mouse corticotroph cell nuclei, which resulted in higher Pomc expression and ACTH secretion, both of which were inhibited by gefitinib. In athymic nude mice, EGFR overexpression enhanced the growth of explanted ACTH-secreting tumors and further elevated serum corticosterone levels. Gefitinib treatment decreased both tumor size and corticosterone levels; it also reversed signs of hypercortisolemia, including elevated glucose levels and excess omental fat. These results indicate that inhibiting EGFR signaling may be a novel strategy for treating Cushing disease.

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“…Pituitary tumors acquire oncogene and tumor suppressor genetic and epigenetic alterations, which result in unrestrained proliferation, aberrant neuroendocrine regulatory signals, and disrupted humoral milieu, mediated directly or indirectly by dysregulated cyclindependent kinases (CDKs) (5,7). Although CDK gene mutations have not readily been identified in human pituitary tumors, overexpression of cyclins and dysregulation of CDK inhibitors are encountered in pituitary adenomas, indicating the importance of CDK activation for potential therapeutic targeting (8,9). However, preclinical studies of CDK inhibitors are hampered by the requirement for large drug quantities and prolonged duration of administration to observe potential efficacy.…”

mentioning

confidence: 99%

Targeting zebrafish and murine pituitary corticotroph tumors with a cyclin-dependent kinase (CDK) inhibitor

Liu

Jiang²,

Ben-Shlomo³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

124

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Cushing disease caused by adrenocorticotropin (ACTH)-secreting pituitary adenomas leads to hypercortisolemia predisposing to diabetes, hypertension, osteoporosis, central obesity, cardiovascular morbidity, and increased mortality. There is no effective pituitary targeted pharmacotherapy for Cushing disease. Here, we generated germline transgenic zebrafish with overexpression of pituitary tumor transforming gene (PTTG/securin) targeted to the adenohypophyseal proopiomelanocortin (POMC) lineage, which recapitulated early features pathognomonic of corticotroph adenomas, including corticotroph expansion and partial glucocorticoid resistance. Adult Tg:Pomc-Pttg fish develop neoplastic coticotrophs and pituitary cyclin E up-regulation, as well as metabolic disturbances mimicking hypercortisolism caused by Cushing disease. Early development of corticotroph pathologies in Tg:Pomc-Pttg embryos facilitated drug testing in vivo. We identified a pharmacologic CDK2/ cyclin E inhibitor, R-roscovitine (seliciclib; CYC202), which specifically reversed corticotroph expansion in live Tg:Pomc-Pttg embryos. We further validated that orally administered R-roscovitine suppresses ACTH and corticosterone levels, and also restrained tumor growth in a mouse model of ACTH-secreting pituitary adenomas. Molecular analyses in vitro and in vivo showed that R-roscovitine suppresses ACTH expression, induces corticotroph tumor cell senescence and cell cycle exit by up-regulating p27, p21 and p57, and downregulates cyclin E expression. The results suggest that use of selective CDK inhibitors could effectively target corticotroph tumor growth and hormone secretion.pituitary cell cycle | pituitary hormone | adrenal function D espite being small (<2 mm) and often undetectable by MRI, pituitary corticotroph tumors are associated with significant morbidities and mortality as a result of adrenal glucocorticoid (Gc) hypersecretion in response to autonomous tumor adrenocorticotropin (ACTH) production (1). The standard of care for Cushing disease consists of transsphenoidal pituitary tumor resection, pituitary-directed radiation, adrenalectomy, and/or medical suppression of adrenal gland cortisol production. Although transsphenoidal ACTH-secreting tumor resection yields 30% to 70% surgical cure rates, adenoma recurrence rate is high (2). Efficacies of other therapeutic modalities are limited by factors such as slow therapeutic response, development of pituitary insufficiency, and uncontrolled pituitary tumor growth in the setting of adrenal gland resection or inhibition (2, 3). Effective pharmacotherapy directly targeting corticotroph tumor growth and/or ACTH production remains a major challenge (4).The pituitary is highly sensitive to cell cycle disruptions (5, 6). Pituitary tumors acquire oncogene and tumor suppressor genetic and epigenetic alterations, which result in unrestrained proliferation, aberrant neuroendocrine regulatory signals, and disrupted humoral milieu, mediated directly or indirectly by dysregulated cyclindependent kinases (CDKs) (5, 7)...

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Cooperation between Cyclin E and p27Kip1 in Pituitary Tumorigenesis

Cited by 80 publications

References 49 publications

Decoding the genetic basis of Cushing's disease: USP8 in the spotlight

Decoding the genetic basis of Cushing's disease: USP8 in the spotlight

EGFR as a therapeutic target for human, canine, and mouse ACTH-secreting pituitary adenomas

Targeting zebrafish and murine pituitary corticotroph tumors with a cyclin-dependent kinase (CDK) inhibitor

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