Oncogenic AKT1(E17K) mutation induces mammary hyperplasia but prevents HER2-driven tumorigenesis

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• The PI3K/Akt pathway is frequently deregulated in breast cancer, often due to mutations in PIK3CA, PTEN, and AKT.
• The somatic AKT1(E17K) mutation is found in 4-8% of breast cancer patients, leading to constitutive Akt activation and promoting uncontrolled proliferation and survival.
• Understanding the role of AKT1(E17K) in mammary tumorigenesis is crucial for developing targeted therapies.

Purpose of the Study:

• To investigate the role of the AKT1(E17K) mutation in mammary gland development and tumorigenesis.
• To elucidate the signaling mechanisms by which AKT1(E17K) influences tumor formation.
• To analyze the impact of AKT1(E17K) on receptor tyrosine kinase (RTK) signaling in breast cancer.

Main Methods:

• Generation of a genetically engineered mouse model conditionally expressing human AKT1(E17K) in the mammary epithelium.
• In vitro studies to assess the activity and signaling dynamics of AKT1(E17K).
• Analysis of mammary gland hyperplasia, tumor development, and estrogen receptor expression in AKT1(E17K) mice.
• Investigation of AKT1(E17K) effects on HER2-driven mammary tumor formation.
• Bioinformatic analysis of TCGA breast cancer data to correlate AKT1(E17K) with RTK expression and phosphorylation.

Main Results:

• Conditional expression of AKT1(E17K) in mouse mammary epithelium induced hyperplasia but not carcinoma in both virgin and multiparous mice.
• AKT1(E17K) exhibited sustained signaling dynamics in vitro despite weak constitutive activity.
• Mammary hyperplasia was associated with increased estrogen receptor expression, but estrogen did not promote tumor development.
• AKT1(E17K) inhibited HER2-driven mammary tumor formation, partly via negative feedback on RTK signaling.
• TCGA data analysis showed decreased mRNA expression, total protein levels, and phosphorylation of RTKs in human tumors with AKT1(E17K).

Conclusions:

• The AKT1(E17K) mutation promotes mammary gland hyperplasia but does not directly cause cancer progression.
• AKT1(E17K) can suppress RTK signaling, including HER2-driven tumorigenesis, through negative feedback mechanisms.
• These findings highlight the complex role of AKT1(E17K) in breast cancer, suggesting it may act as a tumor suppressor in certain contexts by inhibiting RTK signaling.