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

• Published in: Molecular cell 2020-10, Vol.80 (1), p.87-101.e5
• Main Authors: Chen, Xinyu, Ariss, Majd M., Ramakrishnan, Gopalakrishnan, Nogueira, Veronique, Blaha, Catherine, Putzbach, William, Islam, Abul B.M.M.K., Frolov, Maxim V., Hay, Nissim
• Format: Article
• Language: English
• Subjects: Akt1; Akt2; Animals; breast cancer; Carcinogenesis - pathology; Female; Gene Deletion; Humans; insulin; Insulin - metabolism; Isoenzymes - metabolism; Mammary Neoplasms, Animal - enzymology; Mammary Neoplasms, Animal - pathology; metastasis; Neoplasm Metastasis; neutrophils; Neutrophils - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Receptor, ErbB-2 - metabolism; therapy
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2020.08.017

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. [Display omitted] •Akt1 neutrophil-specific deletion is sufficient to inhibit breast cancer metastasis•Akt1 mammary gland-specific deletion inhibits tumor growth but not metastasis•Akt2 mammary gland-specific deletion disables ErbB2 expression in the mammary gland•High insulin after systemic Akt2 deletion prevents mammary tumorigenesis inhibition Chen et al. find that inducible systemic Akt1 deletion after tumor detection inhibits breast cancer metastasis of Akt-proficient tumor by inhibiting tumor-associated neutrophils. Inducible systemic Akt2 deletion does not inhibit breast cancer tumorigenesis and metastasis. Thus, specific Akt1 inhibition could be therapeutic for breast cancer metastasis regardless of tumor origin.