The Function of Akt Isoforms in Breast Cancer Tumorigenesis, Progression and Metastasis

Our previous results suggest that pan-Akt inhibition could exert toxicity indicating that in order to move forward with Akt inhibition for cancer therapy selective Akt isoform inhibitors should be developed. In addition, systemic Akt2 inhibition induces hyperinsulinemia and could hyperactivate the other Akt isoforms to negate the inhibition of Akt. To verify these possibilities, we launched a comprehensive approach to examine cell autonomous and non-cell autonomous effects of inducible Akt1 or Akt2 deletion on mammary tumor development and metastasis in three mouse models of breast cancer. Our studies revealed several surprising and unpredicted results. First, we found that unlike the systemic deletion of Akt1 that inhibits metastasis, the cell autonomous deletion of Akt1 does not inhibit metastasis. Second, unlike the systemic deletion of Akt2 that does not inhibit mammary tumor development, and metastasis, the cell autonomous deletion of Akt2 completely inhibits mammary tumor development. We concluded that the effect of Akt isoforms cell autonomous deletion on mammary tumor development and metastasis is markedly different than that of their systemic deletions. Mechanistically, the systemic effect of Akt1 on metastasis is due to the effect of Akt1 on neutrophils mobilization at the metastatic site. The deletion of Akt2 in the mammary gland is not compatible with Erbb2 expression, but the hyperactivation of Akt1 by the systemic deletion of Akt2 that elevates insulin levels enables Erbb2 expression and does not inhibit mammary tumorigenesis and metastasis.