Sprouty2, PTEN, and PP2A interact to regulate prostate cancer progression
Rachana Patel, … , Owen J. Sansom, Hing Y. Leung
Rachana Patel, … , Owen J. Sansom, Hing Y. Leung
Published February 22, 2013
Citation Information: J Clin Invest. 2013;123(3):1157-1175. https://doi.org/10.1172/JCI63672.
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Research Article Oncology

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

Abstract

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.

Authors

Rachana Patel, Meiling Gao, Imran Ahmad, Janis Fleming, Lukram B. Singh, Taranjit Singh Rai, Arthur B. McKie, Morag Seywright, Robert J. Barnetson, Joanne Edwards, Owen J. Sansom, Hing Y. Leung

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Figure 11

Impact of SPRY2, PTEN, and PP2A status in clinical PC.

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Impact of SPRY2, PTEN, and PP2A status in clinical PC. (A) TMA of clinic...
(A) TMA of clinical PC and BPH cohorts was analyzed for expression of SPRY2 and nuclear and cytoplasmic PTEN. Box and whisker plots show median (lines within boxes), interquartile range (bounds of boxes), and upper and lower range (whiskers). Data were analyzed by ANOVA using Dunnett’s multiple comparison test. (B) Representative IHC images in clinical BPH samples. Scale bars: 100 μm. (C) Kaplan-Meier survival plot for PC patients with reduced SPRY2 expression (below median histoscore); analysis was according to the levels of nuclear PTEN. (D) Heat map of alterations in SPRY2, PTEN, and PPP2CB (PP2A catalytic subunit) generated from metastatic tumors (27 cases) using MSKCC Prostate Oncogenome Project data set from cBio genomic portal. (E) Schematic of PC progression. SPRY2 loss leads to tumor suppression by inducing growth arrest via PP2A-mediated nuclear accumulation of PTEN. Subsequent inactivation of PTEN or PP2A as observed in clinical PC may drive tumor progression.