Cell-Autonomous versus Systemic Akt Isoform Deletions Uncovered New Roles for Akt1 and Akt2 in Breast Cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Metastasis Research

Background:

• The role of Akt isoforms (Akt1, Akt2) in breast cancer tumorigenesis and metastasis is complex and context-dependent.
• Discrepancies exist between cell-autonomous and systemic effects of Akt inhibition on cancer progression.

Purpose of the Study:

• To investigate the distinct roles of cell-autonomous versus systemic Akt1 and Akt2 deletion in mouse models of breast cancer.
• To elucidate the mechanisms by which systemic Akt1 deletion impacts metastasis, particularly concerning tumor-associated neutrophils.
• To evaluate the therapeutic potential of targeting Akt1 for breast cancer metastasis.

Main Methods:

• Utilized three mouse models of breast cancer with inducible deletion of Akt1 or Akt2.
• Employed cell-autonomous and systemic deletion strategies.
• Conducted single-cell mRNA sequencing to analyze cellular composition and gene expression.
• Investigated neutrophil survival and mobilization.

Main Results:

• Systemic Akt1 deletion inhibited metastasis, while cell-autonomous Akt1 deletion did not.
• Systemic Akt1 deletion reduced pro-metastatic neutrophils, impairing their survival and mobilization.
• Systemic or neutrophil-specific Akt1 deletion inhibited metastasis in Akt-proficient tumors.
• Systemic Akt2 deletion exacerbated mammary tumorigenesis and metastasis, whereas cell-autonomous Akt2 deletion prevented ErbB2-driven tumorigenesis.
• Elevated insulin levels due to systemic Akt2 deletion promoted ErbB2-mediated tumorigenesis, which was mitigated by insulin reduction.

Conclusions:

• Systemic Akt1 inhibition is a promising therapeutic strategy against breast cancer metastasis, irrespective of the primary tumor's Akt status.
• Targeting tumor-associated neutrophils via Akt1 inhibition is crucial for controlling metastasis.
• Akt2 plays a dual role, with systemic deletion exacerbating cancer and cell-autonomous deletion being protective in specific contexts, influenced by systemic factors like insulin.