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The Role of Phosphatidylinositol 3' -OH Kinase Signaling in Mammary Tumorigenesis

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Annual summary rept. 1 Jun 2001-1 Jun 2002

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The objective of this research is to elucidate the roles of the phosphatidylinositol 3-OH kinase PI3K and its downstream target Akt kinase in the induction of mammary tumors. To assess the role of Akt in mammary development and tumorigenesis, we generated transgenic mice that express an activated Akt Akt-DD in the mammary epithelium. Although expression of Akt-DD interferes with apoptosis during normal mammary gland involution, mammary tumors are not observed in these strains. To explore the role of Akt in mammary tumorigenesis, mice co-expressing Akt-DD and activated ErbB-2 or a mutant form of Polyomavirus middle T PyV mT antigen de-coupled from PI3KAkt signaling were generated. Co-expression of Akt-DD with mutant PyV mT resulted in dramatic acceleration of mammary tumorigenesis. This acceleration was further correlated with reduced apoptotic cell death, phosphorylation of FKHR and overexpression of cyclin Dl. However, activation of Akt does not to affect metastatic progression. Akt activation also contributes to ErbB- 2 mediated mammary tumori genes is as bi-transgenics co-expressing Akt-DD and activated ErbB-2 transgenes show higher rates of tumorigenesis correlated with increased proliferation and overexpression of cyclin Dl. These observations indicate that Akt activation can impede mammary gland regression and contribute to tumor progression by providing survival and proliferation signals.

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  • Medicine and Medical Research

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