Dataset Information

High Expression of PPM1D Induces Tumors Phenotypically Similar to TP53 Loss-of-Function Mutations in Mice.

ABSTRACT: PPM1D is a negative regulator of p53 and genomic aberrations resulting in increased activity of PPM1D have been observed in cancers of different origins, indicating that PPM1D has oncogenic properties. We established a transgenic mouse model overexpressing PPM1D and showed that these mice developed a wide variety of cancers. PPM1D-expressing mice developed tumors phenotypically and genetically similar to tumors in mice with dysfunctional p53. T-cell lymphoblastic lymphoma was the most frequent cancer observed in these mice (55%) followed by adenocarcinomas (24%), leukemia (12%) and other solid tumors including neuroblastoma. Characterization of T-cell lymphomas in mice overexpressing PPM1D demonstrates Pten-deletion and p53-accumulation similar to mice with p53 loss-of-function. Also, Notch1 mutations which are recurrently observed in T-cell acute lymphoblastic lymphoma (T-ALL) were frequently detected in PPM1D-transgenic mice. Hence, PPM1D acts as an oncogenic driver in connection with cellular stress, suggesting that the PPM1D gene status and expression levels should be investigated in TP53 wild-type tumors.

SUBMITTER: Milosevic J

PROVIDER: S-EPMC8582939 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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High Expression of PPM1D Induces Tumors Phenotypically Similar to TP53 Loss-of-Function Mutations in Mice.

Milosevic Jelena J Fransson Susanne S Gulyas Miklos M Olsen Thale K TK Gallo-Oller Gabriel G Treis Diana D Elfman Lotta H M LHM Wilhelm Margareta M Martinsson Tommy T Baryawno Ninib N Kogner Per P Johnsen John Inge JI

Cancers 20211031 21

PPM1D is a negative regulator of p53 and genomic aberrations resulting in increased activity of PPM1D have been observed in cancers of different origins, indicating that PPM1D has oncogenic properties. We established a transgenic mouse model overexpressing PPM1D and showed that these mice developed a wide variety of cancers. PPM1D-expressing mice developed tumors phenotypically and genetically similar to tumors in mice with dysfunctional p53. T-cell lymphoblast ...[more]

PMID: 34771656

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Project description:Purpose: GATA3 is a transcription factor essential for mammary luminal epithelial cell differentiation. Expression of GATA3 is absent or significantly reduced in basal-like breast cancers. Gata3 loss-of-function impairs cell proliferation, making it difficult to investigate the role of GATA3 deficiency in vivo. We previously demonstrated that CDK inhibitor p18INK4c (p18) is a downstream target of GATA3 and restrains mammary epithelial cell proliferation and tumorigenesis. Whether and how loss-of-function of GATA3 results in basal-like breast cancers remains elusive. Methods: We generated mutant mouse strains with heterozygous germline deletion of Gata3 in p18 deficient backgrounds and developed a Gata3 depleted mammary tumor model system to determine the role of Gata3 loss in controlling cell proliferation and aberrant differentiation in mammary tumor development and progression. Results: Haploid loss of Gata3 reduced mammary epithelial cell proliferation with induction of p18, impaired luminal differentiation, and promoted basal differentiation in mammary glands. p18 deficiency induced luminal type mammary tumors and rescued the proliferative defect caused by haploid loss of Gata3. Haploid loss of Gata3 accelerated p18 deficient mammary tumor development and changed the properties of these tumors, resulting in their malignant and luminal-to-basal transformation. Expression of Gata3 negatively correlated with basal differentiation markers in MMTV-PyMT mammary tumor cells. Depletion of Gata3 in luminal tumor cells also reduced cell proliferation with induction of p18 and promoted basal differentiation. We confirmed that expression of GATA3 and basal markers are inversely correlated in human basal-like breast cancers. Conclusions: This study provides the first genetic evidence demonstrating that loss-of-function of GATA3 directly induces basal-like breast cancer. Our finding suggests that basal-like breast cancer may also originate from luminal type cancer.

Project description:TP53 is a master tumor suppressor gene, mutated in approximately half of all human cancers. Given the many regulatory roles of the corresponding p53 protein, it is possible to infer loss of p53 activity - which may occur due to alterations in trans - from gene expression patterns. Several such alterations that phenocopy p53 loss are known, however additional ones may exist, but their identity and prevalence among human tumors are not well characterized. We perform a large-scale statistical analysis on transcriptomes of ~ 7,000 tumors and ~ 1,000 cell lines, estimating that 12% and 8% of tumors and cancer cell lines, respectively, phenocopy TP53 loss: they are likely deficient in the activity of the p53 pathway, while not bearing obvious TP53 inactivating mutations. While some of these cases are explained by amplifications in the known phenocopying genes MDM2, MDM4 and PPM1D, many are not. An association analysis of cancer genomic scores jointly with CRISPR/RNAi genetic screening data identified an additional common TP53-loss phenocopying gene, USP28. Deletions in USP28 are associated with a TP53 functional impairment in 2.9-7.6% of breast, bladder, lung, liver and stomach tumors, and have comparable effect size to MDM4 amplifications. Additionally, in the known copy number alteration (CNA) segment harboring MDM2, we identify an additional co-amplified gene (CNOT2) that may cooperatively boost the TP53 functional inactivation effect of MDM2. An analysis of cancer cell line drug screens using phenocopy scores suggests that TP53 (in)activity commonly modulates associations between anticancer drug effects and various genetic markers, such as PIK3CA and PTEN mutations, and should thus be considered as a drug activity modifying factor in precision medicine. As a resource, we provide the drug-genetic marker associations that differ depending on TP53 functional status. Human tumors that do not bear obvious TP53 genetic alterations but that phenocopy p53 activity loss are common, and the USP28 gene deletions are one likely cause.

Dataset Information

High Expression of PPM1D Induces Tumors Phenotypically Similar to TP53 Loss-of-Function Mutations in Mice.

Publications

High Expression of <i>PPM1D</i> Induces Tumors Phenotypically Similar to <i>TP53</i> Loss-of-Function Mutations in Mice.

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