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

Abstract

Phosphatidylinositol 3-kinases (PI3K) constitute important regulators of various signaling pathways with relevance in cancer. Enhanced activation of p110A, 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 p110A to the membrane. Different transgenic lines expressing myristoylated p110A 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 myrp110A transgenic mice with heterozygous p53(+/À) 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 myrp110A 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 myrp110A transgenic mice, we observed an increased phosphorylation of the estrogen receptor-A, 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]

Cooperation between Pik3ca and p53 Mutations in Mouse Mammary Tumor Formation

“…Indeed, we observed reduced survival of R26-Pik3-ca H1047R ;p53 f ;MMTV-Cre NLST double-mutant animals. Cooperation between Pik3ca H1047R and p53 loss-of-function mutation is in contrast to the situation observed in MMTV-myrPik3ca mice, in which mammary tumor formation is enhanced by expression of CDK4 R24C but not by deletion of one p53 allele (42). In our model, apoptosis was very low in all of the tumors analyzed.…”

PIK3CA Mutation Associates with Improved Outcome in Breast Cancer

“…Mammary tumors derived from transgenic mice that express a constitutively active p110α show high levels of ERα phosphorylation, an uncommon finding in murine mammary tumors. High levels of ERα phosphorylation identified in preneoplastic epithelium were reduced with PI3K inhibitor therapy (15). The cross-talk between nongenomic ER activities and the PI3K/ Akt pathway may provide a differential target not observed in other PIK3CA mutated tumor types.…”

“…Activated Akt has been shown to enhance the early stages of tumorigenesis while showing a suppressive effect on tumor invasion and metastatic potential (14,15). In bitransgenic mice that express both activated Akt and ErbB2 in the mammary epithelium, accelerated mammary tumor formation and a marked decrease in lung metastasis are observed compared with transgenic mice expressing activated ErbB2 alone (14).…”

Spinophilin loss contributes to tumorigenesis in vivo

“…First, we assessed the maximum and minimum number of epithelial cell layers of the mammary ducts for each mouse line. 21 To this end, the cell layers at the points of the ducts, where the maximum number of cell layers is present, were observed and counted. 21 The average number of epithelial cell layers was higher in both nulliparous and multiparous Spn-null mice (Fig.…”