Irs2 inactivation suppresses tumor progression in Pten+/- mice

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Matthias Szabolcs1, Megan Keniry, Laura Simpson

  • 1Institute for Cancer Genetics, College of Physicians and Surgeons, Columbia University, New York, New York, USA.

The American Journal of Pathology
|December 20, 2008
PubMed

Insights

Loss of PTEN (phosphatase and tensin homologue) normally activates PI3K signaling. However, elevated IRS2 (insulin receptor substrate-2) in PTEN-deficient tumors suggests a role for IRS2 in cancer progression, impacting cell growth and invasion.

Area of Science:

  • Oncology
  • Molecular Biology
  • Signaling Pathways

Background:

  • Mutations in the PTEN/PI3K pathway are common in human cancers.
  • Pten(+/-) mice develop tumors due to PI3K pathway activation.
  • PI3K activation typically downregulates IRS2, but elevated IRS2 is observed in PTEN-compromised tumors.

Purpose of the Study:

  • To investigate the role of IRS2 in tumor progression in the context of PTEN deficiency.
  • To determine if IRS2 contributes to cancer cell growth, proliferation, and invasion.

Main Methods:

  • Crossed Pten(+/-) mice with Irs2(+/-) mice to generate compound heterozygous mice.
  • Analyzed tumor initiation, cancer cell growth, proliferation, and invasion.
  • Assessed the expression of Myc and IRS2 in mouse models and human prostate cancer samples.
  • Utilized cultured cells to study IRS2's effect on MYC expression.

Main Results:

  • Deletion of Irs2 did not affect tumor initiation in Pten(+/-) mice.
  • Irs2 deletion suppressed cancer cell growth, proliferation, and invasion.
  • Irs2 deletion attenuated Myc expression in prostatic intraepithelial neoplasia.
  • IRS2 and MYC expression levels were correlated in human prostate cancer.
  • IRS2 stimulated MYC expression in cultured cells.

Conclusions:

  • The PI3K-activating adaptor IRS2 contributes to tumor progression in Pten(+/-) mice.
  • IRS2 promotes tumor progression by stimulating Myc expression and DNA synthesis.

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