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

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

  • Mol Cell. 2020 Oct 1;80(1):87-101.e5. doi: 10.1016/j.molcel.2020.08.017.
Xinyu Chen 1 Majd M Ariss 1 Gopalakrishnan Ramakrishnan 1 Veronique Nogueira 1 Catherine Blaha 1 William Putzbach 1 Abul B M M K Islam 2 Maxim V Frolov 1 Nissim Hay 3
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60607, USA.
  • 2 Department of Genetic Engineering and Biotechnology, University of Dhaka, Dhaka 1000, Bangladesh.
  • 3 Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60607, USA; Research & Development Section, Jesse Brown VA Medical Center, Chicago, IL 60612, USA. Electronic address: [email protected].
Abstract

Studies in three mouse models of breast Cancer identified profound discrepancies between cell-autonomous and systemic Akt1- or Akt2-inducible deletion on breast Cancer tumorigenesis and metastasis. Although systemic Akt1 deletion inhibits metastasis, cell-autonomous Akt1 deletion does not. Single-cell mRNA sequencing revealed that systemic Akt1 deletion maintains the pro-metastatic cluster within primary tumors but ablates pro-metastatic neutrophils. Systemic Akt1 deletion inhibits metastasis by impairing survival and mobilization of tumor-associated neutrophils. Importantly, either systemic or neutrophil-specific Akt1 deletion is sufficient to inhibit metastasis of Akt-proficient tumors. Thus, Akt1-specific inhibition could be therapeutic for breast Cancer metastasis regardless of primary tumor origin. Systemic Akt2 deletion does not inhibit and exacerbates mammary tumorigenesis and metastasis, but cell-autonomous Akt2 deletion prevents breast Cancer tumorigenesis by ErbB2. Elevated circulating Insulin level induced by Akt2 systemic deletion hyperactivates tumor Akt, exacerbating ErbB2-mediated tumorigenesis, curbed by pharmacological reduction of the elevated Insulin.

Keywords

Akt1; Akt2; breast cancer; insulin; metastasis; neutrophils; therapy.

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