Differential expression of cyclin D1 in human pituitary tumors: relation to MIB-1 and p27/Kip1 labeling indices

Hewedi, Iman H.; Osman, Wesam M.; Mahdy, Manal M. El

doi:10.1016/j.jnci.2011.11.003

Cited by 18 publications

(20 citation statements)

References 34 publications

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“…In particular, the Ki-67 LI, widely used to determine cellular growth fraction in many types of tumors, is accepted as prognostic indicator in pituitary tumors, although controversial results have emerged from clinical studies and criticisms are also reported in the literature (6,11,12,13,14,15). Other markers have been proposed to assess the aggressiveness of PA, among which pituitary tumor transforming gene, p27, p16, galectin-3, and cyclin D1, but none of them has gained general acceptance as prognostic indicator (9,16,17,18,19,20). Therefore, useful predictors of PA behavior remain to be found for appropriate surveillance and treatment.…”

Section: Introductionmentioning

confidence: 99%

Minichromosome maintenance protein 7 as prognostic marker of tumor aggressiveness in pituitary adenoma patients

Coli

Sylvia

Fadda

et al. 2016

European Journal of Endocrinology

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Background: Ki-67 labeling index (LI) is currently regarded as a useful prognostic marker of pituitary adenoma (PA) clinical behavior, although its relevance as a reliable clinical indicator is far from being universally accepted, since both validations and criticisms are found in the literature. Minichromosome maintenance 7 (MCM7), a cell-cycle regulator protein, has been recently proposed as a marker of tumor aggressiveness in tumors from many sites, including the CNS. Therefore, we evaluated MCM7, in comparison to Ki-67, as a potential marker of clinical outcome in PA. Design and methods: In this single-institution retrospective study, 97 patients with PA (23 ACTH, 12 GH, 29 PRL, 10 FSH/LH, and 23 non-secreting adenomas) were recruited and the prognostic value of both MCM7 and Ki-67 was evaluated by immunohistochemical techniques. In addition, p53 nuclear expression and mitotic index were also evaluated. Results: Twenty-six of the 97 PA patients recurred during the follow-up period. Cox's regression analysis showed that high nuclear expression of MCM7 LI, unlike Ki-67 LI, was directly associated with a higher (7.7-fold) risk of recurrence/progression. Kaplan-Meier analysis of recurrence/progression-free survival curves revealed that patients with high MCM7 LI (R15%) had a shorter recurrence/progression-free survival than those with low MCM7 LI (!15%). Moreover, among patients with invasive tumors, high MCM7 LI identified those with the highest risk of recurrence/progression. Conclusions: Data from this study suggest that MCM7 is a prognostic marker of clinical outcome in PA patients, more reliable and informative than Ki-67.

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Section: Introductionmentioning

confidence: 99%

Minichromosome maintenance protein 7 as prognostic marker of tumor aggressiveness in pituitary adenoma patients

Coli

Sylvia

Fadda

et al. 2016

European Journal of Endocrinology

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“…[17] A recent study suggested new functions of cyclin D1, such as stimulation of cell migration and invasion, enhancement of angiogenesis, regulation of transcription factor activation, induction of chromosomal instability, and control of miRNA expression. [14] However, these findings have not been confirmed by further investigations in PCs.…”

Section: Resultsmentioning

confidence: 99%

Genetic aspects of pituitary carcinoma

2016

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Background:Pituitary carcinoma (PC) is a rare type of malignant intracranial neoplasm defined as distant metastasis of pituitary adenoma (PA). Although PC incidence is low because only 0.1% to 0.2% of PAs ultimately develop into PCs, the prognosis is poor and 66% of patients die within the first year. Existing therapeutic measures, including surgical removal, chemotherapy, and radiotherapy, have limited effectiveness. The lack of efficacy of current treatments is largely caused by the limited understanding of the molecular pathogenesis of PA and the malignant transformation to PC. Therefore, the aim of this systematic review was to summarize published research regarding gene and protein expression in PC to clarify the molecular mechanisms underlying PC genesis and development and identify new candidate diagnostic biomarkers and therapeutic targets for potential use in personalized treatment of PC.Methods:We followed the PRISMA guidelines to plan and conduct this systematic review. PubMed, Embase, and Web of Science databases were searched for relevant studies conducted before December 16, 2015 describing the association of PC with gene expression at the mRNA and protein levels. MeSH terms combined with free terms were used to retrieve the references.Results:In total, 207 records were obtained by primary search, and 32 were included in the systematic review. Compared with normal pituitary gland and/or PA, 30 and 18 genes were found to have higher or lower expression, respectively, in PCs using different analytical methods. Among them, we selected 9 upregulated and 7 downregulated genes for further analysis based on their identification as candidate treatment targets in other cancers, potential clinical application, or further research value.Conclusion:Previous studies demonstrated that many genes promote PC malignant transformation, angiogenesis, invasion, metastasis, and recurrence. Although most of these genes and proteins have not been fully analyzed with regard to their downstream mechanisms or potential diagnostic and therapeutic application, they have the potential to become candidate PC biomarkers and/or molecular targets for guiding personalized treatment. Modern advanced technologies should be utilized in future research to identify more candidate genes for PC pathogenesis, as precisely targeted gene therapies against PC are urgently required.

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“…Kip1 expression than does 45 and in multiple PAs by Bamberger et al 6 and Komatsubara et al; 37 more recently, Hewedi et al 27 compared cyclin D1 expression with p27…”

Section: Kip1mentioning

confidence: 97%

“…8 Overexpression of cyclin D1 is known to be present in a large number of neoplasms, both malignant and nonmalignant, and is one of the most common tumorigenic factors. 27 Despite the widespread nature of cyclin D1 overexpression, however, little published investigation into its role in human PA formation has been definitively shown until recently. In 2011, Hewedi et al 27 showed that the expressions of CCND1 and cyclin D1 were elevated in PAs versus those in the normal pituitary gland.…”

Section: Ccnd1/cyclin D1mentioning

confidence: 99%

“…27 Despite the widespread nature of cyclin D1 overexpression, however, little published investigation into its role in human PA formation has been definitively shown until recently. In 2011, Hewedi et al 27 showed that the expressions of CCND1 and cyclin D1 were elevated in PAs versus those in the normal pituitary gland. These results were confirmed by Lee et al 42 in 2014 using IHC staining.…”

Section: Ccnd1/cyclin D1mentioning

confidence: 99%

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Gene and protein expression in pituitary corticotroph adenomas: a systematic review of the literature

Seltzer¹,

Ashton²,

Scotton³

et al. 2015

FOC

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OBJECT Functional corticotroph pituitary adenomas (PAs) secrete adrenocorticotropic hormone (ACTH) and are the cause of Cushing's disease, which accounts for 70% of all cases of Cushing's syndrome. Current classification systems for PAs rely primarily on laboratory hormone findings, tumor size and morphology, invasiveness, and immunohistochemical findings. Likewise, drug development for functional ACTH-secreting PAs (ACTH-PAs) is limited and has focused largely on blocking the production or downstream effects of excess cortisol. The authors aimed to summarize the findings from previous studies that explored gene and protein expression of ACTH-PAs to prioritize potential genetic and protein targets for improved molecular diagnosis and treatment of Cushing's disease. METHODS A systematic literature review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A PubMed search of select medical subject heading (MeSH) terms was performed to identify all studies that reported gene- and protein-expression findings in ACTH-PAs from January 1, 1990, to August 24, 2014, the day the search was performed. The inclusion criteria were studies on functional ACTH-PAs compared with normal pituitary glands, on human PA tissue only, with any method of analysis, and published in the English language. Studies using anything other than resected PA tissue, those that compared other adenoma types, those without baseline expression data, or those in which any pretreatment was delivered before analysis were excluded. RESULTS The primary search returned 1371 abstracts, of which 307 were found to be relevant. Of those, 178 were selected for secondary full-text analysis. Of these, 64 articles met the inclusion criteria and an additional 4 studies were identified from outside the search for a total of 68 included studies. Compared with the normal pituitary gland, significant gene overexpression in 43 genes and 22 proteins was reported, and gene underexpression in 58 genes and 15 proteins was reported. Immunohistochemistry was used in 39 of the studies, and reverse transcriptase polymerase chain reaction was used in 26 of the studies, primarily, and as validation for 4 others. Thirteen studies used both immunohistochemistry and reverse transcriptase polymerase chain reaction. Other methods used included microarray, in situ hybridization, Northern blot analysis, and Western blot analysis. Expression of prioritized genes emphasized in multiple studies were often validated on both the gene and protein levels. Genes/proteins found to be overexpressed in ACTH-PAs relative to the normal pituitary gland included hPTTG1/securin, NEUROD1/NeuroD1 (Beta2), HSD11B2/11β-hydroxysteroid dehydrogenase 2, AKT/Akt, protein kinase B, and CCND1/cyclin D1. Candidate genes/proteins found to be underexpressed in ACTH-PAs relative to the normal pituitary gland included CDKN1B/p27Kip1, CDKN2A/p16, KISS1/kisspeptin, ACTHR/ACTH-R, and miR-493. CONCLUSIONS On the basis of the authors' systematic review, many significant gene and protein targets that may contribute to tumorigenesis, invasion, and hormone production/secretion of ACTH have been identified and validated in ACTH-PAs. Many of these potential targets have not been fully analyzed for their therapeutic and diagnostic potential but may represent candidate molecular targets for biomarker development and drug targeting. This review may help catalyze additional research efforts using modern profiling and sequencing techniques and alteration of gene expression.

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Differential expression of cyclin D1 in human pituitary tumors: relation to MIB-1 and p27/Kip1 labeling indices

Abstract: Expression of cyclin D1 in pituitary tumors is related to cell proliferation, recurrence, and metastatic potential. Nuclear cyclin D1 expression is a good marker of aggressive behavior in pituitary tumors.

Cited by 18 publications

References 34 publications

Minichromosome maintenance protein 7 as prognostic marker of tumor aggressiveness in pituitary adenoma patients

Minichromosome maintenance protein 7 as prognostic marker of tumor aggressiveness in pituitary adenoma patients

Genetic aspects of pituitary carcinoma

Gene and protein expression in pituitary corticotroph adenomas: a systematic review of the literature

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