Allele-specific tumor spectrum in
            <i>Pten</i>
            knockin mice

Wang, Hui; Karikomi, Matt; Naidu, Shan K.; Rajmohan, Ravi; Caserta, Enrico; Chen, Hui-Zi; Rawahneh, Maysoon; Moffitt, Julie; Stephens, Julie; Fernández, Soledad; Weinstein, Michael; Wang, Daqing; Sadée, Wolfgang; Perle, Krista La; Stromberg, Paul C.; Rosol, Thomas J.; Eng, Charis; Ostrowski, Michael C.; Leone, Gustavo

doi:10.1073/pnas.0912524107

Cited by 60 publications

(65 citation statements)

References 26 publications

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“…Supporting this, Chang et al have shown that, independent of its phosphatase activity, nuclear expression of PTEN in PC cells such as LNCaP can inhibit tumorigenesis (25). Also, the phosphatase mutant Pten C124R/+ heterozygous mice showed fewer proliferative lesions in the prostate when compared with Pten +/-mice, underscoring the phosphataseindependent functions of Pten (35).…”

Section: Figurementioning

confidence: 90%

Sprouty2, PTEN, and PP2A interact to regulate prostate cancer progression

Patel¹,

Gao²,

Ahmad³

et al. 2013

J. Clin. Invest.

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Concurrent activation of RAS/ERK and PI3K/AKT pathways is implicated in prostate cancer progression.The negative regulators of these pathways, including sprouty2 (SPRY2), protein phosphatase 2A (PP2A), and phosphatase and tensin homolog (PTEN), are commonly inactivated in prostate cancer. The molecular basis of cooperation between these genetic alterations is unknown. Here, we show that SPRY2 deficiency alone triggers activation of AKT and ERK, but this is insufficient to drive tumorigenesis. In addition to AKT and ERK activation, SPRY2 loss also activates a PP2A-dependent tumor suppressor checkpoint. Mechanistically, the PP2A-mediated growth arrest depends on GSK3β and is ultimately mediated by nuclear PTEN. In murine prostate cancer models, Pten haploinsufficiency synergized with Spry2 deficiency to drive tumorigenesis, including metastasis. Together, these results show that loss of Pten cooperates with Spry2 deficiency by bypassing a novel tumor suppressor checkpoint. Furthermore, loss of SPRY2 expression correlates strongly with loss of PTEN and/or PP2A subunits in human prostate cancer. This underlines the cooperation between SPRY2 deficiency and PTEN or PP2A inactivation in promoting tumorigenesis. Overall, we propose SPRY2, PTEN, and PP2A status as an important determinant of prostate cancer progression. Characterization of this trio may facilitate patient stratification for targeted therapies and chemopreventive interventions.

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Section: Figurementioning

confidence: 90%

Sprouty2, PTEN, and PP2A interact to regulate prostate cancer progression

Patel¹,

Gao²,

Ahmad³

et al. 2013

J. Clin. Invest.

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“…S710F (15,25), Akt1 fl/fl (26), Stat5a/b fl/fl (10), Pten G129E (27), TetO-Cre (28), MMTV-Cre (line A) (29), and MMTV-tTA (30). Stat5a/b fl/fl mice were kindly provided by Lothar Hennighausen (NIH), and TetO-Cre mice (MGI:2679524) were purchased from the Jackson Laboratory.…”

Section: Methodsmentioning

confidence: 99%

“…Mutations in PTEN are responsible for inherited predispositions to cancer such as Cowden syndrome (CS). One of the most frequently diagnosed malignancies in CS patients is breast cancer, and introducing CS-related PTEN mutations into the germ line of mice predisposes females to mammary cancer after a long latency (27). We anticipated that in their role as positive and negative regulators of the PI3K/Akt1 pathway, Stat5 and PTEN might synergistically promote mammary epithelial growth and, perhaps, neoplastic transformation.…”

Section: Dox-inducible Manner (Wap-rtta Teto-stat5mentioning

confidence: 99%

Stat5 Regulates the Phosphatidylinositol 3-Kinase/Akt1 Pathway during Mammary Gland Development and Tumorigenesis

Schmidt

Wehde

Sakamoto

et al. 2014

Molecular and Cellular Biology

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dStat5 (signal transducer and activator of transcription 5) is an essential mediator of cytokine receptor signaling and plays important roles in the proliferation of alveolar progenitors and the survival of functionally differentiated epithelial cells in the mammary gland. A deregulated expression and activation of Stat5 leads to precocious alveolar development in the absence of pregnancy hormones, impaired mammary gland remodeling following the cessation of lactation, and mammary tumor formation. We reported previously that Stat5 induces the transcription of the Akt1 gene from a novel promoter. In this report, we provide experimental evidence that Akt1 is an essential mediator for the biological function of Stat5 as a survival factor. Additionally, Stat5 controls the expression of the regulatory and catalytic subunits of the phosphatidylinositol 3-kinase (PI3K) (p85␣ and p110␣), thereby greatly augmenting signaling through the prosurvival PI3K/Akt pathway. In agreement with this model, we observed that the constitutive activation of Stat5 cooperates with the loss of function of the tumor suppressor PTEN by accelerating the formation of preneoplastic lesions and mammary tumors. The mammary gland-specific ablation of Stat5 is sufficient to prevent mammary carcinogenesis in a genuine mouse model for Cowden syndrome. Therefore, targeting the Jak2/Stat5 pathway might be a suitable strategy to prevent breast cancer in patients that carry a mutant PTEN allele. S tat5a (signal transducer and activator of transcription 5a) was first identified as a prolactin (PRL)-responsive DNA binding protein in mammary epithelial cells (1, 2). Shortly after the discovery of Stat5a, Liu and colleagues (3) isolated another highly conserved Stat5 transcript from the mouse mammary gland, which they named Stat5b. Although both Stat5 proteins share an overall 96% amino acid similarity and are activated upon PRL stimulation, gene deletion studies in knockout mice revealed that only Stat5a is essential for the development of secretory mammary epithelial cells during pregnancy and lactation (4-6). The predominant role of Stat5a in this tissue is likely a consequence of the dissimilar expression of the two Stat5 proteins. This notion is supported by the fact that a compensatory upregulation of Stat5b can partially restore normal alveolar development in Stat5a knockout females (7). The two Stat5 proteins have therefore redundant functions, and a lack of both genes results in more severe developmental defects that affect the genesis of luminal epithelial progenitors (8). These abnormalities phenocopy a deficiency in the Janus kinase 2 (Jak2), which is required for the PRL-mediated activation of Stat5a and Stat5b (9,10). In addition to their essential functions for the formation of luminal progenitors, Jak2 and Stat5 are equally important for the survival of functionally differentiated epithelial cells during late pregnancy and lactation (9, 10).Within only a few days following the cessation of lactation and weaning of the offspring, the mammary ...

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“…In mice, mutations that affect the regulation of PTEN or TSC2 display abnormal activation of AKT signaling and develop a neoplasia phenotype that is reminiscent of the human syndromes (Pollizzi et al, 2009;Alimonti et al, 2010b;Wang et al, 2010), which is milder than that observed in PTEN +/-or TSC1/2 +/-mice. In the case of spontaneous tumor formation, it is homozygous loss of PTEN or the TSC proteins that is seen in tumor progression.…”

Section: Perspectivementioning

confidence: 99%

“…Cowden disease patients with mutations that decrease PTEN levels have a corresponding increase in AKT activity and exhibit increased formation of gastrointestinal polyps (Trotman et 4 (3/80) 2 (1/60) 3-10 (1/30, 9/91) Philp et al, 2001;Mizoguchi et al, 2004;Parsons et al, 2008 p110 ( Almoguera et al, 1988;Smit et al, 1988;Suzuki et al, 1990;Burmer et al, 1991;Boughdady et al, 1992;Lemoine et al, 1992 Cheng et al, 1992;Bellacosa et al, 1995;Ruggeri et al, 1998;Snijders et al, 2003;Parsons et al, 2005;Pedrero et al, 2005;Nakayama et al, 2006;Nakayama et al, 2007; Hashimoto et al, 2004;CGARN, 2008;Ichimura et al, 2008Ichimura et al, al., 2007. In mice, mutations that affect the regulation of PTEN or TSC2 display abnormal activation of AKT signaling and develop a neoplasia phenotype that is reminiscent of the human syndromes (Pollizzi et al, 2009;Alimonti et al, 2010b;Wang et al, 2010), which is milder than that observed in PTEN +/-or TSC1/2 +/-mice. In the case of spontaneous tumor formation, it is homozygous loss of PTEN or the TSC proteins that is seen in tumor progression.…”

Section: Disease Models and Mechanisms Dmmmentioning

confidence: 99%

From man to mouse and back again: advances in defining tumor AKTivities in vivo

Restuccia

Hemmings

2010

Disease Models &Amp; Mechanisms

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AKT hyperactivation is a common event in human cancers, and inhibition of oncogenic AKT activation is a major goal of drug discovery programs. Mouse tumor models that replicate AKT activation typical of human cancers provide a powerful means by which to investigate mechanisms of oncogenic signaling, identify potential therapeutic targets and determine treatment regimes with maximal therapeutic efficacy. This Perspective highlights recent advances using in vivo studies that reveal how AKT signaling supports tumor formation, cooperates with other mutations to promote tumor progression and facilitates tumor-cell dissemination, focusing on well-characterized prostate carcinoma mouse models that are highly sensitive to AKT activation. The implications of these findings on the therapeutic targeting of AKT and potential new drug targets are also explored. Disease Models & Mechanisms DMMPK) (Feng et al., 2004) stimulates full AKT activity. Full activation of AKT leads to additional substrate-specific phosphorylation events, including inhibitory phosphorylation of the proapoptotic FOXO proteins. Dephosphorylation of Ser473 by the PH-domain leucinerich repeat-containing protein phosphatases PHLPP1 and PHLPP2, and the conversion of PtdIns(3,4,5)P 3 to PtdIns(3,4)P 2 by PTEN, inhibits AKT signaling.Human tumors commonly display amplification or overexpression of cell-surface receptors or signaling molecules that activate the PI3K-PTEN-AKT pathway, activating mutations of PI3K, loss of expression of the negative regulator PTEN and/or mutation of AKT (Fig. 1). These mutations account for findings that the AKT pathway is activated in a high proportion of tumors, in a wide variety of tissues; a selection of these findings are summarized in Table 1. From man to mouse: elucidating oncogenic AKT signaling in miceMouse models are invaluable tools for understanding how mutations in PI3K-PTEN-AKT signaling contribute to tumorigenesis in human cancer. In humans, mild mutations in PTEN, TSC1 or TSC2 result in familial tumor-susceptibility syndromes, and a similar neoplasia is seen when the mild mutations are modeled in mice. By contrast, human biopsies of spontaneous tumors that display PTEN, TSC1 or TSC2 loss have increased AKT signaling compared with biopsies of tumors from patients with familial syndromes. This increased AKT signaling and the corresponding more severe tumor development are reflected in mouse models that have heterozygous and homozygous loss of PTEN, TSC1 or TSC2. These studies highlight the contribution that mouse models of AKT activation can make in elucidating oncogenic AKT signaling in familial and spontaneous neoplasia. Human tumor-susceptibility syndromes and neoplasia phenotypes in miceIn humans, mutations in PTEN (which is upstream of AKT), or in TSC1 or TSC2 (which are downstream of AKT), result in complex disease syndromes such as Cowden disease or tuberous sclerosis (Table 2). These diseases display a variety of symptoms (for reviews, see Eng, 2003;Zhou et al., 2003;Crino et al., 2006), because various poi...

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Allele-specific tumor spectrum in Pten knockin mice

Cited by 60 publications

References 26 publications

Sprouty2, PTEN, and PP2A interact to regulate prostate cancer progression

Sprouty2, PTEN, and PP2A interact to regulate prostate cancer progression

Stat5 Regulates the Phosphatidylinositol 3-Kinase/Akt1 Pathway during Mammary Gland Development and Tumorigenesis

From man to mouse and back again: advances in defining tumor AKTivities in vivo

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