Abstract
Phosphatidylinositol 3-kinases (PI3K) constitute important regulators of various signaling pathways with relevance in cancer. Enhanced activation of p110alpha, 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 p110alpha to the membrane. Different transgenic lines expressing myristoylated p110alpha 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 myrp110alpha 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 myrp110alpha 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 myrp110alpha 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-alpha pathway inhibition.
Highlights
The family of phosphatidylinositol 3-kinases (PI3K) plays a central role in transducing a variety of extracellular stimuli into a wide range of cellular processes, including cell cycle progression, cell growth, survival, cell adhesion, and cell motility
Because it has been described that AKT activation leads to delayed mammary gland involution [10, 11], we investigated if the elevated PI3K activity in our transgenic mouse lines had similar functional consequences
We observed a mild increase in preneoplastic lesions and tumors in the membrane-bound p110a transgenic mice, they mostly fail to progress to carcinoma, unlike the lesions of mice with specific PTEN deletion in mammary glands [7]
Summary
The family of phosphatidylinositol 3-kinases (PI3K) plays a central role in transducing a variety of extracellular stimuli into a wide range of cellular processes, including cell cycle progression, cell growth, survival, cell adhesion, and cell motility. When activated by cell surface receptors, PI3K regulates the phosphoinositide lipid metabolism and the production of phosphatidylino-. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org). Doi:10.1158/0008-5472.CAN-08-1539 sitol 3,4,5-triphosphate (PIP3) at the plasma membrane. The production of PIP3 facilitates the recruitment of AKT via its pleckstrin homology domain, leading to its phosphorylation at Thr308 and Ser473. As the primary downstream mediator, AKT transmits the PI3K signal to a large number of molecules thereby diversifying the PI3K signal into various functional outcomes. PTEN is a dual protein/lipid phosphatase, the main substrate of which is PIP3, the product of PI3K. Loss of PTEN function results in the accumulation of PIP3, mimicking the effect of PI3K activation
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