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Noncatalytic PTEN missense mutation predisposes to organ-selective cancer development in vivo

Enrico Caserta1, Onur Egriboz1, Hui Wang1

  • 1Solid Tumor Biology Program, James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Genetics, College of Arts and Sciences, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Virology, Immunology, and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA;

Genes & Development
|August 26, 2015
PubMed

Insights

A phosphatase and tensin homology deleted on chromosome 10 (PTEN) mutation, Pten(FV), impacts tumor suppression independently of AKT signaling. This study reveals organ-selective cancer development linked to this PTEN mutation in mice.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Inactivation of phosphatase and tensin homology deleted on chromosome 10 (PTEN) is a known driver of cancer via increased PI3K-AKT signaling.
  • PTEN's tumor suppressor role is critical in regulating cell growth and preventing tumorigenesis.

Purpose of the Study:

  • To investigate the in vivo tumor suppressor function of a PTEN C2 domain missense mutation (Pten(FV)), identified in human cancers.
  • To determine if this mutation affects AKT signaling and leads to organ-selective cancer development.

Main Methods:

  • Generation and analysis of Pten knock-in mice harboring the Pten(FV) mutation.
  • Assessment of AKT signaling pathways in Pten(FV/FV) and Pten(FV/+) mice.
  • Histopathological examination of various organs for carcinoma development.

Main Results:

  • Homozygous Pten(FV/FV) embryos showed normal development despite reduced PTEN protein and intact AKT signaling.
  • Heterozygous Pten(FV/+) mice developed carcinoma in specific organs (thymus, stomach, adrenal medulla, mammary gland) but not others.
  • Tumor progression in sensitive organs occurred without overt AKT activation, while uterine cancer required secondary AKT activation.

Conclusions:

  • The Pten(FV) mutation exhibits a tumor suppressor function independent of canonical AKT signaling inhibition.
  • This PTEN mutation predisposes to organ-selective cancer development through mechanisms distinct from AKT pathway activation.
  • Understanding this novel tumor suppressor function is crucial for targeted cancer therapies.
Keywords:
F341Vbreastcancerendometriumptenuterus

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