Simultaneous haploinsufficiency of Pten and Trp53 tumor suppressor genes accelerates tumorigenesis in a mouse model of prostate cancer

Couto, Suzana; Cao, Mei; Duarte, Paulo César Xavier; Banach‐Petrosky, Whitney; Wang, Shunyou; Romanienko, Peter; Wu, Hong; Cardiff, Robert D.; Abate‐Shen, Cory; Cunha, Gerald R.

doi:10.1016/j.diff.2008.09.010

Cited by 31 publications

(27 citation statements)

References 44 publications

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“…Because GEM models with loss-of-function of Trp53 alone have modest prostate cancer phenotypes (20,24,25), whereas those with loss-of-function of Pten alone develop prostate adenocarcinoma and CRPC (21,26), we compared the phenotype of Trp53 and Pten compound mutant mice with that of Pten single mutant mice. In particular, we analyzed the prostate phenotype of two different inducible GEM models, corresponding to Nkx3.1 CreERT2/+ ; Pten flox/flox ; Trp53 flox/flox mice ( NPp53 mice) and Nkx3.1 CreERT2/+ ; Pten flox/flox mice ( NP mice, previously described (26)) under normal androgen conditions (hormonally-intact mice), or following androgen-ablation by surgical castration (Fig.…”

Section: Resultsmentioning

confidence: 99%

Transdifferentiation as a Mechanism of Treatment Resistance in a Mouse Model of Castration-Resistant Prostate Cancer

et al. 2017

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Current treatments for castration-resistant prostate cancer (CPRC) that target androgen receptor (AR) signaling improve patient survival, yet ultimately fail. Here we provide novel insights into treatment response for the anti-androgen abiraterone by analyses of a genetically-engineered mouse model (GEMM) with combined inactivation of Trp53 and Pten, which are frequently co-mutated in human CRPC. These NPp53 mice fail to respond to abiraterone, and display accelerated progression to tumors resembling treatment-related CRPC with neuroendocrine differentiation (CRPC-NE) in humans. Cross-species computational analyses identify master regulators of adverse response that are conserved with human CRPC-NE, including the neural differentiation factor SOX11, which promotes neuroendocrine differentiation in cells derived from NPp53 tumors. Furthermore, abiraterone-treated NPp53 prostate tumors contain regions of focal and/or overt neuroendocrine differentiation, distinguished by their proliferative potential. Notably, lineage-tracing in vivo provides definitive and quantitative evidence that focal and overt neuroendocrine regions arise by transdifferentiation of luminal adenocarcinoma cells. These findings underscore principal roles for TP53 and PTEN inactivation in abiraterone resistance and progression from adenocarcinoma to CRPC-NE by transdifferentiation.

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Section: Resultsmentioning

confidence: 99%

Transdifferentiation as a Mechanism of Treatment Resistance in a Mouse Model of Castration-Resistant Prostate Cancer

et al. 2017

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“…Cancerous lesions, mainly prostatic intraepithelial neoplasia (PIN), were graded from I to IV (Fig. S4 shows representative sections) (19,20). Analysis of H&E-stained sections of all prostate lobes in 5-to 7-mo-old mice shows that KI/cPten F/F mice had a lower incidence of high grade PIN (represented by PIN IV lesions) than WT/ cPten F/F mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

eIF4E phosphorylation promotes tumorigenesis and is associated with prostate cancer progression

Furic

Liang

Larsson

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

447

547

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Translational regulation plays a critical role in the control of cell growth and proliferation. A key player in translational control is eIF4E, the mRNA 5′ cap-binding protein. Aberrant expression of eIF4E promotes tumorigenesis and has been implicated in cancer development and progression. The activity of eIF4E is dysregulated in cancer. Regulation of eIF4E is partly achieved through phosphorylation. However, the physiological significance of eIF4E phosphorylation in mammals is not clear. Here, we show that knock-in mice expressing a nonphosphorylatable form of eIF4E are resistant to tumorigenesis in a prostate cancer model. By using a genome-wide analysis of translated mRNAs, we show that the phosphorylation of eIF4E is required for translational up-regulation of several proteins implicated in tumorigenesis. Accordingly, increased phospho-eIF4E levels correlate with disease progression in patients with prostate cancer. Our findings establish eIF4E phosphorylation as a critical event in tumorigenesis. These findings raise the possibility that chemical compounds that prevent the phosphorylation of eIF4E could act as anticancer drugs. PTEN | translational controlA berrations in the control of mRNA translation initiation have been documented in many tumor types (1-4). Translation initiation is controlled in part by eIF4E, the mRNA 5′ cap-binding protein. eIF4E is a proto-oncogene, inasmuch as its overexpression in immortalized rodent fibroblasts or human epithelial cells causes transformation (5, 6), and in mouse models its overexpression engenders tumor formation (7,8). eIF4E is phosphorylated by the MNK1/2 serine/threonine kinases, which are activated in response to mitogenic and stress signaling downstream of ERK1/2 and p38 MAP kinase, respectively (9, 10). eIF4E phosphorylation at serine 209 by MNK1/2 promotes its transformation activity (11,12). To study the role of eIF4E phosphorylation in tumorigenesis in the whole organism, we generated a knock-in (KI) mouse in which eIF4E serine 209 was mutated to alanine. Here, we show that mouse embryonic fibroblasts (MEFs) isolated from eIF4E S209A/S209A embryos display a marked resistance to oncogene-induced transformation. Furthermore, the mutant mice are viable, but are resistant to development of Pten loss-induced prostate cancer, and this resistance is associated with a decrease in MMP3, CCL2, VEGFC, and BIRC2 proteins. Moreover, eIF4E is highly phosphorylated in hormone-refractory prostate cancer, which correlates with poor clinical outcome. These results demonstrate the importance of eIF4E phosphorylation in tumorigenesis and validate the eIF4E phosphorylation pathway as a potential therapeutic target for cancer. ResultsSer209 Is the Only Phosphorylation Site in eIF4E. To address the role of eIF4E phosphorylation in tumorigenesis, a knock-in (KI) mouse in which serine 209 was replaced by an alanine residue was generated. The strategy and targeting vector construction for the generation, selection, and genotyping of the S209A mice is shown in Fig. S1. The eIF4E S...

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“…Studies with knockout mice indicate that Pten haploinsufficiency contributes to tumorigenesis either alone or by cooperating with other genetic alterations. For example, prostatic intraepithelial neoplasia develops in heterozygous Pten knockout mice, although tumor incidence increases in mice with heterozygous knockout of both Pten and Tp53 , even when the corresponding wild-type alleles are retained [65]. …”

Section: Mechanisms Of Akt Activation In Cancermentioning

confidence: 99%

Diverse Mechanisms of AKT Pathway Activation in Human Malignancy

Cheung

Testa

2013

CCDT

157

117

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AKT/PKB (Protein Kinase B) are central proteins mediating signals from receptor tyrosine kinases and phosphatidylinositol 3-kinase. AKT kinases are involved in a number of important cellular processes including cell proliferation and survival, cell size in response to nutrient availability, tumor invasion/metastasis, and angiogenesis. Various components of the AKT signaling pathway are encoded by tumor suppressor genes and oncogenes whose loss or activation, respectively, plays an important role in tumorigenesis. The growing body of evidence connecting deregulated AKT signaling with sporadic human cancers and inherited cancer predisposition syndromes is discussed. We also highlight new findings regarding the involvement of activating mutations of AKT1, AKT2, and AKT3 in somatic overgrowth disorders: Proteus syndrome, hypoglycemia with hypertrophy, and hemimegalencephaly, respectively. In addition, we review recent literature documenting the various ways the AKT signaling pathway is activated in human cancers and consequences for molecularly targeted therapies.

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Simultaneous haploinsufficiency of Pten and Trp53 tumor suppressor genes accelerates tumorigenesis in a mouse model of prostate cancer

Cited by 31 publications

References 44 publications

Transdifferentiation as a Mechanism of Treatment Resistance in a Mouse Model of Castration-Resistant Prostate Cancer

Transdifferentiation as a Mechanism of Treatment Resistance in a Mouse Model of Castration-Resistant Prostate Cancer

eIF4E phosphorylation promotes tumorigenesis and is associated with prostate cancer progression

Diverse Mechanisms of AKT Pathway Activation in Human Malignancy

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