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Knock in of the AKT1 E17K mutation in human breast epithelial cells does not recapitulate oncogenic PIK3CA mutations

J Lauring1, D P Cosgrove, S Fontana

  • 1Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. jlaurin1@jhmi.edu

Oncogene
|January 27, 2010
PubMed

Insights

The AKT1 E17K mutation, found in cancers, surprisingly had minimal effects in a new breast cell model. This suggests other genetic events are needed for PI3K pathway activation in these cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • An oncogenic AKT1 mutation (G49A:E17K) is identified in human breast, colon, and ovarian cancers.
  • Limited functional analysis exists due to the rarity of cancer cell lines with this specific mutation.

Purpose of the Study:

  • To establish a physiologic in vitro model for studying the AKT1 G49A:E17K mutation.
  • To investigate the functional consequences of this specific AKT1 mutation in a human breast epithelial cell line.

Main Methods:

  • Somatic cell gene targeting was employed.
  • The nontumorigenic human breast epithelial cell line MCF10A was used.
  • Knock-in of the E17K mutation into the AKT1 gene was performed.

Main Results:

  • Knock-in of AKT1 E17K resulted in minimal phenotypic consequences.
  • The mutation did not recapitulate biochemical or growth characteristics observed with PIK3CA mutations.
  • Functional analysis revealed differences compared to PIK3CA hotspot mutations.

Conclusions:

  • Mutations within the PI3-kinase (PI3K) pathway are not functionally equivalent.
  • The AKT1 E17K mutation alone may not be sufficient for oncogenic PI3K pathway activation.
  • Cooperative genetic events might be required for cancers with the AKT1 E17K mutation.

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