Targeting Breast Cancers Featuring Activating Mutations in PIK3CA by Generating a Lethal Dose of PIP3

摘要

The level of PIP3 is tightly regulated by the activities of two opposing enzymes, phosphatidylinositol 3-kinase (PI3K) and Phosphatase and tensin homolog (PTEN), acting as 'on/off' switches. We hypothesized that PI3K activity is tolerated within a relatively narrow window in cells - 'too much of PIP3 is just as lethal as too little', thus PIK3CA/PTEN double mutants may elevate PIP3 to a lethal level. To test this hypothesis, we determined the effect of PTEN inactivation in human mammary epithelial cells carrying activated alleles of PIK3CA. We also generated a Tet-regulated transgenic mouse mammary tumor model expressing oncogenic PIK3CA and produced mammary tumor induced by mammary gland specific loss of PTEN. We are now ready to test our hypothesis in vivo with concurrent activation of PIK3CA and inactivation of PTEN.