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Molatore, S. ; Kügler, A. ; Irmler, M. ; Wiedemann, T. ; Neff, F. ; Feuchtinger, A. ; Beckers, J. ; Robledo, M.* ; Roncaroli, F.* ; Pellegata, N.S.

Characterization of neuroendocrine tumors in heterozygous mutant MENX rats: A novel model of invasive medullary thyroid carcinoma.

Endocr. Relat. Cancer 25, 145-162 (2018)
Publ. Version/Full Text Postprint DOI PMC
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Rats affected by the MENX syndrome spontaneously develop multiple neuroendocrine tumors (NETs) including adrenal, pituitary and thyroid gland neoplasms. MENX was initially reported to be inherited as a recessive trait and affected rats were found to be homozygous for the predisposing Cdkn1b mutation encoding p27. We here report that heterozygous MENX-mutant rats (p27+/mut) develop the same spectrum of NETs seen in the homozygous (p27mut/mut) animals but with slower progression. Consequently, p27+/mut rats have a significantly shorter lifespan compared with their wild-type (p27+/+) littermates. In the tumors of p27+/mut rats, the wild-type Cdkn1b allele is neither lost nor silenced, implying that p27 is haploinsufficient for tumor suppression in this model. Transcriptome profiling of rat adrenal (pheochromocytoma) and pituitary tumors having different p27 dosages revealed a tissue-specific, dose-dependent effect of p27 on gene expression. In p27+/mut rats, thyroid neoplasms progress to invasive and metastatic medullary thyroid carcinomas (MTCs) accompanied by increased calcitonin levels, as in humans. Comparison of expression signatures of late-stage vs early-stage MTCs from p27+/mut rats identified genes potentially involved in tumor aggressiveness. The expression of a subset of these genes was evaluated in human MTCs and found to be associated with aggressive RET-M918T-positive tumors. Altogether, p27 haploinsufficiency in MENX rats uncovered a novel, representative model of invasive and metastatic MTC exploitable for translational studies of this often aggressive and incurable cancer.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Menx ; Medullary Thyroid Cancer ; P27 Haploinsufficiency; Multiple Endocrine Neoplasia; Sprague-dawley Rats; Nonfunctioning Pituitary-adenomas; Beta-tubulin Isotypes; Gene-expression; Ret Protooncogene; Kinase Inhibitor; Animal-models; Mice Lacking; In-vivo
Language english
Publication Year 2018
Prepublished in Year 2017
HGF-reported in Year 2017
ISSN (print) / ISBN 1351-0088
e-ISSN 1479-6821
Journal Endocrine-Related Cancer
Quellenangaben Volume: 25, Issue: 2, Pages: 145-162 Article Number: , Supplement: ,
Publisher BioScientifica
Publishing Place Bristol
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Cancer (IDC)
Institute of Pathology (PATH)
Institute of Experimental Genetics (IEG)
CF Pathology & Tissue Analytics (CF-PTA)
Research Unit Analytical Pathology (AAP)
POF-Topic(s) 30201 - Metabolic Health
30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
30505 - New Technologies for Biomedical Discoveries
30205 - Bioengineering and Digital Health
Research field(s) Helmholtz Diabetes Center
Enabling and Novel Technologies
Genetics and Epidemiology
PSP Element(s) G-502590-001
G-500300-001
G-500600-004
G-500600-001
A-630600-001
G-500390-001
G-500600-006
DOI 10.1530/ERC-17-0456
WOS ID WOS:000425596400019
Scopus ID 85042592889
PubMed ID 29142006
Erfassungsdatum 2017-11-22
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