Activation of Phosphatidylinositol 3-Kinase by Membrane Localization of p110α Predisposes Mammary Glands to Neoplastic Transformation

Phosphatidylinositol 3-kinases (PI3K) constitute important regulators of various signaling pathways with relevance in cancer. Enhanced activation of p110 alpha, the catalytic subunit of PI3K, was found in a high proportion of many human tumor types. We generated a mouse model in which PI3K is activated by forced recruitment of p110 alpha to the membrane. Different transgenic lines expressing myristoylated p110 alpha protein under the control of the epithelial-specific mouse mammary tumor virus promoter were selected according to different levels of PI3K activity and characterized. Delayed mammary gland involution and morphologic changes of the mammary ducts could be detected in young transgenic female mice. These changes were more pronounced in old animals, especially in mutiparous females, in which we observed increased ductal branching, alveolar hyperplasia, and intraductal neoplasia. We also observed a small percentage of mammary tumors. Crosses of myrp110 alpha transgenic mice with heterozygous p53(+/-) knockout mice resulted in neither enhanced tumorigenesis nor in a stronger mammary gland phenotype. However, the CDK4 activating mutation (R24C) lead to increased tumorigenesis in transgenic myrp110 alpha mice, emphasizing the postulated perturbation of the interaction of the CDK4/Rb/E2F cascade and the PI3K signaling in many human cancers. Interestingly, in tumors of myrp110 alpha transgenic mice, we observed an increased phosphorylation of the estrogen receptor-alpha, a typical feature of human breast cancer. The model presented here will help to discover additional factors which influence the progression of preneoplastic lesions to tumors in the mammary gland and to explore antitumor therapies based on PI3K or estrogen receptor-a pathway inhibition. [Cancer Res 2008;68(23):9643-53]