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Characterization of neuroendocrine tumors in heterozygous mutant MENX rats: a novel model of invasive medullary thyroid carcinoma [thyroid]

ABSTRACT: CDKN1B (p27) was formally established as a tumor suppressor gene (tsg) following the identification of inactivating germline mutations in rats (MENX syndrome) and patients (MEN4 syndrome) developing multiple neuroendocrine tumors (NETs). MENX-affected rats are homozygous for the predisposing p27 mutation, suggesting a canonical tsg function. In contrast, mice heterozygous for a defective Cdkn1b allele are already predisposed to tumor formation (haploinsufficiency). We here report that heterozygous mutant rats (p27+/mut) develop the same NETs seen in the homozygous (p27mut/mut) animals but with slower progression. In the tumors of p27+/mut rats, the wild-type allele is neither lost nor silenced, implying that p27 is haploinsufficient for tumor suppression also in this model. Transcriptome profiling of rat NETs 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 versus 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 associated with aggressive RET-M918T-positive tumors. Altogether, p27 haploinsufficiency in MENX rats uncovered a novel, representative model of invasive/metastatic MTC, exploitable for translational studies of this aggressive and often incurable cancer.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE98546 | GEO | 2017/11/15

SECONDARY ACCESSION(S): PRJNA385488

REPOSITORIES: GEO

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Characterization of neuroendocrine tumors in heterozygous mutant MENX rats: a novel model of invasive medullary thyroid carcinoma [adrenal]

Project description:As overwhelming evidence coming from transgenic mouse models but also from MEN4 patients seem to suggest that loss or inactivation of a single p27 allele plays an important role in neuroendocrine tumorigenesis, we decided to perform a detailed analysis of the phenotype of rats heterozygous for the MENX-associated germline Cdkn1b mutation. We here show that the reduction to a single functional p27 allele predisposes MENX heterozygous rats to the development of neuroendocrine malignancies.

2017-11-15 | GSE53365 | GEO

Characterization of neuroendocrine tumors in heterozygous mutant MENX rats: a novel model of invasive medullary thyroid carcinoma [pituitary]

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Deletion of Cdkn1b in ACI rats perturbs mammary progenitor cell proliferation and differentiation through non-cell-autonomous mechanisms

Project description:Emerging data indicate that breast epithelial stem cells and progenitors, particularly those in the luminal epithelial cell lineage, are the cells-of-origin of breast carcinomas, and factors that influence breast cancer risk may alter the number and/or properties of these cells. We hypothesize that a subset of p27+ cells represent hormone-responsive progenitors that are quiescent due to the high activity of TGFβ signaling in these cells. The Estrogen-induced mammary tumor model in ACI inbred rats is physiologically relevant rodent model of breast cancer. In the present study we successfully generated Cdkn1b knockout ACI rats and performed comprehensive phenotypic assessment and RNAseq profiling using FACS sorted basal (CD24+CD29high) and luminal (CD24+CD29low) cell populations to characterize Cdkn1b+/+ and Cdkn1b-/- females in prepubertal and adult cohorts. We found that p27KO rats exhibited mammary differentiation phenotype and reduced numbers of mammary epithelial progenitor pool, Interestingly, p27 ablation has the most pronounced effect on luminal progenitor cell gene expression, and milk protein genes and pStat5 were dramatically upregulated, while PR and FoxA1 were greatly downregulated in Cdkn1b-/- luminal cells. Further characterization of mammary glands of prepubertal Cdkn1b knockout rats by fat pad transplantation illustrated p27 deletion in the mammary cancer susceptible ACI rat strain induced mammary epithelial cell differentiation through cell non-autonomous mechanisms.

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| phs000579 | dbGaP

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2016-06-01 | GSE75449 | GEO

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Project description:Transcriptome analysis of effect of Lockd knockout on cells Many long non-coding (lnc) RNAs are reported to regulate gene expression and protein functions. However, the proportion of lncRNAs with biological activities among the thousands expressed in mammalian cells is controversial. We studied Lockd (Downstream of p27), a 434 bp polyadenylated lncRNA originating 4 kb 3â to the Cdkn1b gene. Heterozygous and homozygous deletion of the 25 kb Lockd locus reduced Cdkn1b transcription by approximately 35 and 70% respectively in a mouse erythroid cell line. In contrast, homozygous insertion of a polyadenylation cassette 80 bp downstream of the Lockd transcription start site reduced the entire lncRNA transcript level by > 90%, but had no effect on Cdkn1b transcription. The 5â region of the Lockd gene contains a DNase hypersensitive site, binds numerous transcription factors (TFs), and physically associates with the Cdkn1b promoter in chromosomal conformation capture (NG Capture-C) studies. Thus, the Lockd gene positively regulates Cdkn1b transcription through an enhancer-like cis element and not via the lncRNA transcript. These findings demonstrate that the biological functions of a lncRNA cannot be inferred simply from phenotypes that arise after deleting the corresponding genomic locus. We analyzed mouse G1E erythroid cell line clones with Control Lockd (C - 3 replicates) and with Lockd deletion with CRISPR (KO - 4 replicates) using Mouse Gene 2.0 ST Array platform (transcript version). Array data was processed by RMA algorithm.

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