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PTEN/PI3K/AKT constitutes an important pathway regulating the signalling of multiple biological processes such as apoptosis, metabolism, cell proliferation and cell growth. PTEN is a dual protein/lipid phosphatase which its main substrate, phosphatidyl-inositol 3,4,5 triphosphate (PIP3), is the product of PI3K. Increases in PIP3 recruit AKT to the membrane where it is activated by other kinases that are also dependent on PIP3. Many components of this pathway have been described as causal forces in cancer. PTEN activity is lost by mutation, deletion or promoter silencing by methylation at high frequency in many primary and metastatic human cancers. Germline mutations of PTEN are found in several familial cancer predisposition syndromes. Genetically modified mice have confirmed these PTEN activities. Tissue specific deletions of PTEN usually provoke cancer. Moreover, an absence of PTEN cooperates with an absence of p53 to promote cancer. Recently, activating mutations in the PI3KCA gene (coding for the p110α catalytic subunit of PI3K) have been described in human tumors. Activation of PI3K (and AKT) are reported to occur in breast, ovarian, pancreatic, esophageal and other cancers.
 To better understand the role of PI3K activation in tumorigenesis in vivo, we generated a transgenic mouse model that expresses a myristoylated p110α protein (the catalytic subunit of PI3K) under the control of the epithelial-specific MMTV promoter. We established several transgenic mice lines which have increased PI3K activity. The increased activity of PI3K leads to differences in epithelial cell proliferation by 9 weeks of age, as well as significant alterations of the mammary gland at time of death. Despite the preneoplastic lesions, no progression to tumorigenesis was observed. Neither the additional mammary-specific expression of CyclinD1 nor the concomitant deletion of one p53-allele in the presence of increased PI3K activity lead to an alteration of the mammary gland phenotype observed in these transgenic mice.
 In summary, we produced in a mouse model the increased recruitment of p110α to the membrane with concomitant activation of PI3K, but unlike mice with a PTEN deletion, these mice do not develop tumors. We propose that other PI3K-independent PTEN effector/s is/are responsible for a second signal involved in PTEN-dependent tumorigenesis.

99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA