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

Rachana Patel1, Meiling Gao, Imran Ahmad

  • 1The Beatson Institute for Cancer Research, Glasgow, United Kingdom.

The Journal of Clinical Investigation
|February 26, 2013
PubMed

Insights

Loss of SPRY2 in prostate cancer activates a tumor suppressor checkpoint, but PTEN loss cooperates with SPRY2 deficiency to drive tumor growth and metastasis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Prostate cancer progression involves concurrent activation of RAS/ERK and PI3K/AKT pathways.
  • Negative regulators like sprouty2 (SPRY2), protein phosphatase 2A (PP2A), and phosphatase and tensin homolog (PTEN) are frequently inactivated.

Purpose of the Study:

  • To elucidate the molecular basis of cooperation between genetic alterations in SPRY2, PTEN, and PP2A in prostate cancer.
  • To investigate the role of SPRY2 deficiency in tumor suppressor checkpoints and its interaction with PTEN loss.

Main Methods:

  • Utilized murine prostate cancer models to study the synergistic effects of Spry2 and Pten deficiency.
  • Analyzed the activation of AKT, ERK, PP2A, and GSK3β pathways in response to genetic alterations.
  • Correlated SPRY2, PTEN, and PP2A expression levels in human prostate cancer samples.

Main Results:

  • SPRY2 deficiency alone activates AKT and ERK but is insufficient for tumorigenesis, instead triggering a PP2A-dependent tumor suppressor checkpoint.
  • PTEN haploinsufficiency synergizes with Spry2 deficiency in mouse models, driving prostate tumorigenesis and metastasis.
  • Loss of SPRY2 expression strongly correlates with loss of PTEN and/or PP2A subunits in human prostate cancer.

Conclusions:

  • Loss of PTEN cooperates with SPRY2 deficiency by bypassing a novel tumor suppressor checkpoint, promoting prostate cancer progression.
  • The interplay between SPRY2, PTEN, and PP2A is a critical determinant of prostate cancer progression.
  • Assessing the status of SPRY2, PTEN, and PP2A may aid in stratifying patients for targeted therapies and chemoprevention.

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