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Subtle variations in Pten dose determine cancer susceptibility: Gene expression profiling of a Ptenhy/+ mouse model

ABSTRACT: Subtle variations in Pten dose determine cancer susceptibility: Gene expression profiling for MEF cells from a Ptenhy/+ mouse model. We have analyzed the survival and tumor spectrum in a population of Pten ‘hypermorphic’ mice (Ptenhy/+), which express approximately 80% of total Pten protein. Notably, the Ptenhy/+ developed a spectrum of tumors of variable latencies, with breast tumors occurring at the highest penetrance. Surprisingly, all breast tumors analyzed retain two intact copies of Pten, and maintain Pten protein levels above that observed in heterozygosity. Importantly, subtle down-regulation of Pten was found to alter the expression profile of genes involved in cell proliferation. Taken together, our findings support the notion that initiation of tumorigenesis can occur in the absence of genetic hits, thereby questioning the uniqueness of a saltatory model for cancer susceptibility. In order to understand whether subtle variations in Pten level may affect pathways involved in tumorigenesis, we analyzed the genome-wide expression profile of Ptenhy/+ mouse embryonic fibroblasts (MEFs).

ORGANISM(S): Mus musculus

PROVIDER: GSE20316 | GEO | 2010/02/15

SECONDARY ACCESSION(S): PRJNA125491

REPOSITORIES: GEO

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Subtle variations in Pten dose determine cancer susceptibility: Gene expression profiling of a Ptenhy/+ mouse model

Project description:Subtle variations in Pten dose determine cancer susceptibility: Gene expression profiling for MEF cells from a Ptenhy/+ mouse model. We have analyzed the survival and tumor spectrum in a population of Pten âhypermorphicâ mice (Ptenhy/+), which express approximately 80% of total Pten protein. Notably, the Ptenhy/+ developed a spectrum of tumors of variable latencies, with breast tumors occurring at the highest penetrance. Surprisingly, all breast tumors analyzed retain two intact copies of Pten, and maintain Pten protein levels above that observed in heterozygosity. Importantly, subtle down-regulation of Pten was found to alter the expression profile of genes involved in cell proliferation. Taken together, our findings support the notion that initiation of tumorigenesis can occur in the absence of genetic hits, thereby questioning the uniqueness of a saltatory model for cancer susceptibility. In order to understand whether subtle variations in Pten level may affect pathways involved in tumorigenesis, we analyzed the genome-wide expression profile of Ptenhy/+ mouse embryonic fibroblasts (MEFs). In the Ptenhy/+ mouse model, mice are born with approximately 80% of total Pten protein and are viable and normally fertile. To decrease the expression level of Pten below homozygosity, we targeted intron 3 of Pten with a neomycin (Neo) cassette, under the control of the strong CMV promoter, thereby taking advantage of transcriptional interference. Next, we intercrossed Pten hy/+ mice with Pten+/- mice to generate cohorts of hypomorphic littermate mice with decreasing levels of Pten expression as follows: Ptenwt > Ptenhy/+ > Pten+/- >Ptenhy/- mice littermates. To preserve a constant 129/C57BL/6 mixed genetic background, we have crossed Pten hy/+ mice with Pten +/- for more than seven generations prior to analysis. As expected, Ptenhy/+ mouse embryonic fibroblasts (MEFs) display a level of Pten protein below Ptenwt and above Pten+/- .

2010-02-21 | E-GEOD-20316 | biostudies-arrayexpress

Mus musculus

Project description:Subtle variations in Pten dose determine cancer susceptibility: Gene expression profiling of a Ptenhy/+ mouse model

| PRJNA125491 | ENA

Multifocal demyelinating motor neuropathy associated with a de novo PTEN mutation

Project description:Phosphatase and tensin homolog (PTEN) is a tumour suppressor gene associated with inherited tumour susceptibility conditions, macrocephaly, autism, ataxia, tremor and epilepsy. Functional implications of this protein have been investigated in Parkinson’s and Alzheimer’s diseases. We describe the first patient presented with multifocal demyelinating motor neuropathy in association with a de novo PTEN mutation. The pathogenicity of the mutation was supported by altered expression of several proteins involved in tumorigenesis and fibroblasts showed a reversible defect in catalytic activity of PTEN against the secondary substrate, phosphatidylinositol 3,4,-trisphosphate, suggesting a novel and potentially treatable mechanism for multi-focal demyelinating motor neuropathy.

2018-10-22 | PXD008014 | Pride

PTENa/b paradoxically promote carcinogenesis through WDR5-H3K4me3 axis

Project description:PTEN, a widely investigated tumor suppressor, has at least two longer translational variants, PTEN and . However, the regulation and precise roles of endogenous PTEN/ in tumorigenesis remain greatly unknown. Here we show that USP9X and FBXW11 selectively regulate the stability of PTEN/ but not PTEN proteins by deubiqitination and ubiquitination respectively. USP9X promotes and FBXW11 suppresses tumorigenesis mediated by PTEN/. In contrast to the current paradigm for PTEN as a tumor suppressor, PTEN/ promote tumorigenesis of cancer cells in a phosphatase-independent manner. Mechanistically, PTEN/ localized in the nucleus regulate expressions of tumor-promoting genes such as NOTCH3 in the similar way as the H3K4 presenter WDR5. Further, PTEN/ but not PTEN directly interact with WDR5 to promote trimethylation of H3K4 and maintain a tumor-promoting signature. Taken together, our results indicate that PTEN/ are a double-edged sword for carcinogenesis, suggesting that reinterpretation of the importance of PTEN gene in carcinogenesis is warranted.

2019-11-14 | PXD013196 | Pride

Phosphoproteomics of MEFs with loss-of-function PTEN mutations

Project description:The PTEN tumor suppressor controls cell death and survival by regulating functions of various molecular targets. Whilst the role of PTEN lipid-phosphatase activity on PtdIns(3,4,5)P3 and inhibition of PI3K pathway is well characterized, the biological relevance of PTEN protein-phosphatase activity remains undefined. Using knock-in (KI) mice harbouring cancer-associated and functionally relevant missense mutations, we show that although loss of PTEN lipid-phosphatase function cooperates with oncogenic PI3K to promote rapid mammary tumorigenesis, the additional loss of PTEN protein-phosphatase activity triggered an extensive cell death response evident in early and advanced mammary tumors. Omics and drug-targeting studies revealed that PI3Ks act to reduce glucocorticoid receptor (GR) levels, which are rescued by loss of PTEN protein-phosphatase activity to restrain cell survival. The dual regulation of GR by PI3K and PTEN functions as a rheostat that can be exploited for the treatment of PTEN-loss driven cancers.

2020-10-15 | PXD016184 | Pride

Transcription profiling of PTEN-deficiency in luminal MMTV-ErbB-2 mouse model to investigate its effect on mammary tumorigenesis and metastasis

Project description:Overexpression and/or amplification of the ErbB-2 oncogene, as well as inactivation of the tumor suppressor PTEN, are two important genetic events in human breast carcinogenesis. To address the biological impact of conditional inactivation of PTEN on ErbB-2-induced mammary tumorigenesis, we generated a novel transgenic mouse model that utilizes the MMTV promoter to directly couple expression of activated ErbB-2 and Cre recombinase to the same mammary epithelial cell (MMTV-NIC). Disruption of PTEN in the mammary epithelium of the MMTV-NIC model system dramatically accelerated the formation of multifocal and highly metastatic mammary tumors, which exhibit homogenous pathology. PTEN-deficient/NIC tumorigenesis was associated with an increase in angiogenesis. Moreover, inactivation of PTEN in the MMTV-NIC mouse model resulted in hyperactivation of the PI3K/Akt signalling pathway. However, like the parental strain, tumors obtained from PTEN-deficient/NIC mice displayed histopathological and molecular features of the luminal-like subtype of breast cancer. Taken together, our findings provide important implications in understanding the molecular determinants of mammary tumorigenesis driven by PTEN deficiency and ErbB-2 activation, and could provide a valuable tool for testing the efficacy of therapeutic strategies that target these critical signalling pathways. Experiment Overall Design: Common reference design. 9 samples (including 2 normal tissue and 7 tumor tissue samples) replicated twice as dye swaps, generating a total of 18 arrays.

2009-07-03 | E-GEOD-13916 | biostudies-arrayexpress

Expression data from conditional Klf5 knockout Pten-null mouse prostates

Project description:KLF5 is a basic transcription factor that regulates multiple biological processes, but its function in tumorigenesis appears contradictory in the current literature, with some studies showing tumor suppressor activity and others showing tumor promoting activity. In this study, we examined the function of Klf5 in prostatic tumorigenesis using mice with prostate specific deletion of Klf5 and Pten, both of which are frequently deleted in human prostate cancer. Histological and molecular analyses demonstrated that when one Pten allele was deleted, which causes mouse intraepithelial neoplasia (mPIN), Klf5 deletion accelerated the emergence and progression of mPIN. When both Pten alleles were deleted, which causes prostate cancer, Klf5 deletion promoted tumor growth and caused more severe morphological and molecular alterations, and homozygous deletion of Klf5 was more effective than hemizygous deletion. Unexpectedly, while Klf5 deletion clearly promoted tumorigenesis in luminal cells, it actually diminished the numbers of Ck5-positive basal cells in the Pten-null tumors. Klf5 deletion also increased the cell proliferation rate in tumors with Pten deletion, which involved extensive activation of the PI3K/AKT and MAPK mitogenic signaling pathways and inactivation of the p15 cell cycle inhibitor. Global gene expression and pathway analyses demonstrated that multiple mechanisms could be responsible for the tumor promoting effect of Klf5 deletion, We used microarrays to detail the global programme of gene expression of Klf5-wildtype and Klf5-null mouse dorsal prostates under Pten-null context to figure out the differential expression profiling underlying tumorigenesis 4 Klf5-wildtype and 4 Klf5-null mouse (6 months age) dorsal prostates under Pten-null context were used for RNA extraction and hybridization on Affymetrix mouse st 1.0 array

2014-06-21 | E-GEOD-58719 | biostudies-arrayexpress

PTEN-deficiency in luminal MMTV-ErbB-2 mouse model results in dramatic acceleration in mammary tumorigenesis/metastasis

2009-06-29 | GSE13916 | GEO

Particulate radiation-induced gliomas

Project description:Trangenic mice with brain-targeted deletion of one allele of p53 and one allele ot Pten were irradiated with particulate radiation. Radiation induced gliomas were analyzed to identify copy number variations

2019-07-01 | GSE130677 | GEO

PTEN heterozygosity promotes tumorigenesis in a Smoothened active mouse model of medulloblastoma

Project description:Recent publications have described an important role for cross talk between PI-3 kinase and sonic hedgehog signaling pathways in the pathogenesis of medulloblastoma. Our primary objective was to determine if loss of Pten promotes medulloblastoma tumor formation. When mice expressing SmoA1 were crossed with mice heterozygous for Pten, SmoA1 +; Pten +/- mice exhibited decreased survival, an increased incidence, and a shorter time to onset of symptoms, compared to SmoA1 +; Pten +/+ mice. Tumors from SmoA1 +; Pten +/+ mice exhibited classic histology. In contrast, tumors from SmoA1 +; Pten +/- mice exhibited predominantly nodular/desmoplastic histology and evidence of neuronal differentiation. Analysis by gene expression microarray revealed a clear separation of gene signatures, with upregulation of genes such as Pik3cb, Mapk8, Frap1, and multiple genes involved in angiogenesis in SmoA1+; Pten +/- tumors. Downregulated genes included Pten, Trp53, and Rb1. Western blotting and immunohistochemical analysis revealed decreased expression of Pten and increased activation of Akt in the SmoA1+; Pten +/- tumors. Consistent with these findings, we detected strong expression of PCNA throughout the Pten +/+ tumors and focal areas of intense staining for PCNA in tumors from SmoA1 +/-; Pten +/- mice. Conversely, staining for Cleaved Caspase 3 revealed multiple punctuate foci in SmoA1 +; Pten +/+ tumors and almost no staining in SmoA1 +/-; Pten +/- tumors. These results suggest that increased signaling through PI-3 kinase pathways promotes MB tumorigenesis by driving proliferation and inhibiting apoptosis of granule neuron precursor cells in the developing cerebellum.

2009-11-21 | GSE19059 | GEO

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