Functional analysis of non-hotspot AKT1 mutants found in human breast cancers identifies novel driver mutations:...

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• The phosphatidylinositol 3-kinase (PI3-kinase)-Akt-mTOR pathway is frequently altered in breast cancer and is a target for drug development.
• Personalized cancer therapies aim to use genetic mutations to guide treatment selection.
• Large-scale sequencing studies are uncovering new genetic variants in cancer genes, including those with unknown significance.

Purpose of the Study:

• To functionally analyze six non-hotspot AKT1 pleckstrin homology domain mutants found in breast cancer.
• To determine if these novel AKT1 mutants activate the PI3-kinase pathway and contribute to oncogenesis.

Main Methods:

• Functional assays were used to assess Akt1 activation in the absence of growth factors.
• Analysis included examining downstream target phosphorylation and Akt1 membrane localization.
• Cellular transformation assays were performed to evaluate oncogenic potential.

Main Results:

• Three of the six AKT1 mutants demonstrated constitutive activation of Akt1.
• These active mutants led to downstream protein phosphorylation and constitutive membrane localization, similar to the known E17K mutation.
• The same three mutants exhibited oncogenic activity in cellular transformation assays, while the other three were inactive.

Conclusions:

• These findings validate novel driver mutations in the AKT1 gene.
• The study expands the known repertoire of mutations that activate the PI3-kinase pathway in human breast cancers.
• This work supports the identification of new therapeutic targets for breast cancer treatment.