Training Entitled Development and Characterization of Transgenic Mice With Mammary Gland Specific Expression of the Tumor Suppressor

摘要

The signal transduction protein phosphatidylinositol 3-kinase (PI3K) phosphorylates membrane constituent phosphatidylinositols, producing second messengers that link membrane bound receptor signals to cellular proliferation and survival. The dysregulation of the PI3K signal transduction pathway has been associated with tumorigenesis. The tumor suppressor PTEN/MMACl is a multispecific phosphatase that is a major negative regulator of PI3K, and PTEN/ MMACl is frequently mutated in advanced cancers. We have produced four breast- targeted transgenic mouse models that express either the PTEN/MMACl wild-type or phosphatase-inactive proteins under the control of either the murine mammary tumor virus (MMTV) promoter or the whey acidic protein (WAP) promoter. These models are being characterized as part of our effort to understand the role of PTEN in breast tumorigenesis. In addition to these models, we have employed cell line model systems to further define the role PTEN/MMACl in PI3K signaling. We have determined that, dependent on the culture conditions, PTEN/MMACl expression can induce either apoptosis or cell cycle arrest in breast cancer cell lines and that loss of PTEN/MMACl is associated with an increase in the duration of ligand-induced signaling through the PI3K pathway. Our results are supportive of PTEN/MMACl being a breast tumor suppressor that functions by regulating the PI3K signaling pathway.