The Role of Phosphatidylinositol 3' -OH Kinase Signaling in Mammary Tumorigenesis
Abstract
The objective of this research is to elucidate the roles of the phosphatidylinositol 3'-OH kinase (PI3K) and its downstream targets such as the Akt kinase in the induction of mammary tumors. To assess the role of Akt in mammary development and tumorigenesis, we have 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 a mutant form of Polyomavirus middle T (PyV mT) antigen de-coupled from PI3K/Akt 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 D1. However, activation of Akt does not to affect metastatic progression. Aid activation may also be able to contribute to ErbB-2 mediated mammary tumorigenesis as bi-transgenics co-expressing Akt-DD and activated ErbB-2 transgenes show higher rates of tumorigenesis. Taken together these observations indicate that Aid activation can impede mammary gland regression and contribute to tumor progression by providing an important cell survival signal.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2001
- Accession Number
- ADA396606
Entities
People
- John N Hutchinson
- William A Muller
Organizations
- McMaster University