Class IA phosphatidylinositol 3-kinases (PI3Ks) are activated by growth factor receptor tyrosine kinases (RTKs) and Ras to generate the primary intracellular lipid signal, phosphatidylinositol 3,4,5-trisphosphate (PIP3), essential for multiple cellular processes, including survival, proliferation and differentiation. The tumor suppressor PTEN, a lipid phosphatase, dephosphorylates PIP3 and therefore counteracts the action of PI3Ks. Constitutive activation of the class IA PI3K signaling pathway via direct or indirect mutagenic events is amongst the most frequent events in human breast cancer. Thus, class 1A PI3Ks are attractive targets for therapeutic intervention in breast cancer. In mammals, there are two class 1A PI3K catalytic isoforms, p110? and p110?, which are ubiquitously expressed in epithelial tissues/organs, among other sites. Despite their similarity in molecular structure and enzymatic activity, recent studies suggest that the two isoforms have distinct functions in cell signaling and oncogenic transformation. However, we have very limited understanding of the specific functions for each type of PI3K. All class IA PI3Ks display the same sensitivity to the classical PI3K inhibitors wortmannin and LY294002. Mice lacking p110? or p110? are early embryonic lethal, which precluded further delineation of their specific functions. We recently generated conditional knockout animals for the p110? and p110? genes via the Cre/loxP recombination system to facilitate the study of class 1A PI3Ks. In this application, we want to test our hypothesis that p110? and p110? have distinct biological roles in mammary epithelium function and tumorigenesis. This hypothesis leads to predictions that we propose to test in cell culture and animal models.
The Specific Aims are as follows. 1. To test the prediction that p110? and p110? have distinct roles in signal transduction and cell proliferation in mouse mammary epithelial cells (MMECs). 2. To test the prediction that p110? and p110? have distinct roles in mammary gland development. 3. To test the prediction that p110? and p110? have distinct functions in breast tumorigenesis driven by oncogenic Her2/Neu. These studies will advance our understanding of the functions of PI3K isoforms and provide information critical to developing effective, specific and less toxic PI3K inhibitors for cancer treatment.
The Class IA PI3K signaling pathway is hyper-activated in a high percentage of human cancers, including breast, brain and colon cancers, and is also highly suited for pharmacologic intervention. However, because PI3K activity is involved in multiple fundamental physiological functions, there is a considerable risk that its inhibition may have toxic side effects. The information derived from this study will not only provide us with comprehensive knowledge of PI3K isoforms in normal breast tissue function and tumor pathogenesis, but will also help us to evaluate critical drug targets to facilitate the development of more specific and less toxic drugs for breast cancer treatment.
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