Constitutively Activated PI3K Signaling Accelerates Tumor Initiation and Progression in Breast and Lung Cancers

Phosphatidylinositol 3-kinase (PI3K) is a major positive regulator of the PI3K signaling pathway that regulates many important cellular functions including growth, proliferation, survival, metabolism, and angiogenesis. The PIK3CA gene, encoding the p110alpha catalytic subunit of the PI3K, is frequently mutated in a variety of human tumors including breast and lung cancers. Here, we have generated a mouse model with a Cre-recombinase-mediated knock-in of myristoylated PIK3CA (myr-p110alpha ) into Rosa26 locus. This mouse model showed gain-of-function by rendering p110 alpha protein to the plasma membrane. Constitutively activated PI3K induced by myr-p110alpha led to embryonic lethality at E9.5~11.5. The myr-p110alphawt/fl mice demonstrated developmental defects, and hemorrhage in embryos and the extraembryonic yolk sac. Interestingly, mosaic expression of EIIa-Cre;myr-p110alpha/ wt/fl increased tumor predisposition both in male and female. These finding demonstrate the importance of PI3K signaling in embryonic development, normal vessel integrity during development, and tumorigenesis. The embryonic lethality associated with expression of myr-p110alpha mutation during development likely explains the lack of inherited germline PIK3CA mutations in humans.;PIK3CA have been proposed to play a role in tumor initiation rather than progression as they are found in both pre-invasive and advanced forms of invasive cancer. In order to study the role of constitutively active PI3K signaling in tumor initiation and/or progression, we utilized a recombinant adenovirus expressing Cre-recombinase (Ad-Cre), allowing tissue-specific expression of the transgene in the mammary glands or lungs of p53f/fll ;KrasG12D mice, in the absence or in the presence of myr-p110alpha mutation. To this end, we demonstrated that addition of heterozygous myr-p110alpha mutation significantly accelerated tumor initiation but not progression, while addition of homozygous myr-p110alpha mutation greatly promoted both tumor initiation and progression in a breast cancer model. Similarly, addition of one copy of myr-p110alpha markedly promoted early tumor development in the lung leading to decreased mice survival from tumor growth. The results shown in this thesis suggest a clear link between oncogenic PI3K signaling activation and tumor initiation, and use of our mouse model will provide valuable information that can be applied to the clinic to target the PI3K signaling pathway.