MENX and MEN4

Pellegata, Natalia S.

doi:10.6061/clinics/2012(sup01)04

Cited by 43 publications

(42 citation statements)

References 26 publications

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“…MENX is a multitumor syndrome in the rat caused by a biallelic loss-of-function mutation in Cdkn1b, encoding the cell-cycle inhibitor p27 (25). MENX-affected rats (mutant) develop gonadotroph pituitary adenomas with complete penetrance and represent the only spontaneous model of such tumors.…”

Section: Introductionmentioning

confidence: 99%

Targeting PI3K/mTOR Signaling Displays Potent Antitumor Efficacy against Nonfunctioning Pituitary Adenomas

Lee

Wiedemann

Groß

et al. 2015

Clinical Cancer Research

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Purpose: Novel therapeutic approaches are needed to improve the postoperative management of residual nonfunctioning pituitary adenomas (NFPA), given their high relapse rate. Here, we evaluated the antitumor efficacy of the dual PI3K/mTOR inhibitor NVP-BEZ235 in the only available model of spontaneous NFPAs (MENX rats).Experimental Design: Organotypic cultures of rat primary NFPAs were incubated with NVP-BEZ235 and assessed for cell viability, proliferation, apoptosis, and PI3K/mTOR inhibition. NVP-BEZ235, or placebo, was administered to MENX rats and tumor response was monitored noninvasively by diffusion weighted-magnetic resonance imaging (DW-MRI). Following treatment, tumor tissues were investigated for cell proliferation, apoptosis, and PI3K/mTOR inhibition. Genes mediating the cytotoxic activity of NVP-BEZ235 were identified by gene-expression profiling. Among them, Defb1, encoding beta-defensin 1, was further studied for its role in pituitary cells and in human pancreatic neuroendocrine tumor (NET) cells.Results: NVP-BEZ235 showed antiproliferative and pro-cell death activities against NFPAs both in vitro and in vivo, and the response to the drug correlated with inhibition of the PI3K pathway. DW-MRI identified early functional changes (decreased cellularity) in the adenomas before their size was affected and emerged as a useful modality to assess therapy response. The cytotoxic effect of PI3K/mTOR blockade in NFPA was mediated by several genes, including Defb1. NVP-BEZ235 treatment induced Defb1 expression in NFPAs in vitro and in vivo, and in pancreatic NET cells. High Defb1 levels sensitized NET cells to PI3K/mTOR inhibition.Conclusions: Our findings provide rationale for clinical investigation of PI3K/mTOR inhibition in NFPAs and identify novel effectors of PI3K-mediated neuroendocrine cell survival.

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Section: Introductionmentioning

confidence: 99%

Targeting PI3K/mTOR Signaling Displays Potent Antitumor Efficacy against Nonfunctioning Pituitary Adenomas

Lee

Wiedemann

Groß

et al. 2015

Clinical Cancer Research

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“…AtT20 cells transfected with p27-V109G show a 50% increase in the number of colonies when compared with either cells transfected with p27-wt or with empty vector, while both variant proteins show similar growth suppression of GH3 cells (B). (Pellegata et al 2006, Georgitsi et al 2007, Agarwal et al 2009, Marinoni & Pellegata 2010, Pellegata 2012. While this article was under revision, somatic mutations and deletions of CDKN1B were reported in a subset of neuroendocrine tumors of the small intestine (Francis et al 2013).…”

Section: Discussionmentioning

confidence: 99%

“…p27 is mutated in a MEN syndrome both in rats and human patients (Pellegata et al 2006, Marinoni & Pellegata 2010. The germline mutations in CDKN1B so far identified in patients (12 in total) affect the stability of p27 protein, its localization, its ability to interact with partner proteins, or the efficiency of transcription of the mutated CDKN1B allele (Pellegata 2012). Usually, p27 is not somatically mutated, but its expression is reduced or lost in more than 50% of all human tumors, including endocrine tumors (Chu et al 2008).…”

Section: Introductionmentioning

confidence: 99%

p27 variant and corticotropinoma susceptibility: a genetic and in vitro study

Sekiya

Bronstein

Benfini

et al. 2014

Endocrine-Related Cancer

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Germline mutations in p27 kip1 are associated with increased susceptibility to multiple endocrine neoplasias (MEN) both in rats and humans; however, the potential role of common polymorphisms of this gene in endocrine tumor susceptibility and tumorigenesis remains mostly unrecognized. To assess the risk associated with polymorphism rs2066827 (p27-V109G), we genotyped a large cohort of Brazilian patients with sporadic endocrine tumors (pituitary adenomas, nZ252; pheochromocytomas, nZ125; medullary thyroid carcinoma, nZ51; and parathyroid adenomas, nZ19) and 885 population-matched healthy controls and determined the odds ratios and 95% CIs. Significant associations were found for the group of patients with pituitary adenomas (PZ0.01), particularly for those with ACTH-secreting pituitary adenomas (PZ0.005). In contrast, no association was found with GH-secreting pituitary tumors alone or with the sporadic counterpart of MEN2-component neoplasias. Our in vitro analyses revealed increased colony formation and cell growth rate for an AtT20 corticotropin mouse cell line overexpressing the p27-V109G variant compared with cells transfected with the WT p27. However, the genotypic effects in genetic and in vitro approaches were divergent. In accordance with our genetic data showing specificity for ACTH-secreting pituitary tissues, the overexpression of p27-V109G in a GH3 somatotropin rat cell line resulted in no difference compared with the WT. Pituitary tumors are one of the major clinical components of syndromes associated with the p27 pathogenic mutations MENX and MEN4. Our genetic and in vitro data indicate that the common polymorphism rs2066827 may play a role in corticotropinoma susceptibility and tumorigenesis through a molecular mechanism not fully understood thus far.

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“…Distinct MEN2 subtypes have been recognized. [1][2][3][4][5] MEN2A is the most common form of MEN2 and its first manifestation is often MTC, usually occurring between the ages of 20 and 30 years. 6 MEN2A is characterized by MTC and pheochromocytoma plus primary hyperparathyroidism.…”

Section: Introductionmentioning

confidence: 99%

A rare missense variant in RET exon 8 in a Portuguese family with atypical multiple endocrine neoplasia type 2A

Martins

Vale

et al. 2016

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baCKgROUND aND ObJECTIvE: multiple Endocrine Neoplasia type 2 (mEN2) is a rare genetic disorder characterized by medullary thyroid carcinoma (mTC), pheochromocytoma and primary hyperparathyroidism. mEN2 is an autosomal dominant syndrome caused by mutations in the RET proto-oncogene. In the vast majority of patients, the mutations are localized in exons 10, 11 and 13-15 of the RET gene. Rare variants located in exon 8 were recently identified but their clinical significance remains unclear. DESIgN aND mEThODS: We studied two sisters presenting with pheochromocytoma as the first tumor. One of the sisters was diagnosed with a right pheochromocytoma at the age of 44 and at age 53 she developed an invasive left pheochromocytoma with no other endocrine neoplasia. The other sister was diagnosed with a left pheochromocytoma at age 50 and at age 64 she had a right phemochromocytoma and mTC. Neither of the two sisters presented evidence of primary hyperparathyroidism. mutations of the RET proto-oncogene were investigated by DNa sequencing. RESUlTS: We detected a germline missense variant in RET exon 8 (p.Cys531arg) in both sisters. The p.Cys531arg variant was not present in a third 50-year-old sister who has remained to date clinically unaffected. CONClUSION: This is the first case showing the p.Cys531arg variant in RET exon 8 co-segregating with family members affected by a syndrome reminiscent of mEN2a. Our results suggest that this variant has a specific genotype-phenotype correlation as it is associated with the development of pheochromocytoma before the onset of mTC.

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MENX and MEN4

Cited by 43 publications

References 26 publications

Targeting PI3K/mTOR Signaling Displays Potent Antitumor Efficacy against Nonfunctioning Pituitary Adenomas

Targeting PI3K/mTOR Signaling Displays Potent Antitumor Efficacy against Nonfunctioning Pituitary Adenomas

p27 variant and corticotropinoma susceptibility: a genetic and in vitro study

A rare missense variant in RET exon 8 in a Portuguese family with atypical multiple endocrine neoplasia type 2A

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