The Role of Phosphaditvl Inositol-3' Kinase Coupled Signaling Pathways in Mammary Tumorigenesis
Abstract
The major focus of DOD sponsored research program is to assess the role of the phosphadityl inositol 3f (PI-3f) and Akt-1 kinases in mammary tumorigenesis and metastasis. Although evidence suggests roles for phosphatidylinositol 3f-OH kinase (PI3K) and Akt in normal mammary development and tumorigenesis (Farrelly et al., 1999; Stambolic et al., 1998; Webster et al., 1998),the role of these signaling molecules in these processes remains to be elucidated. To directly assess the role of Akt and PI-3f kinase in mammary epithelial development and tumorigenesis, we have generated transgenic mice that express a constitutively active Akt (Akt-DD) or PI-3f kinase in the mammary epithelium. To accomplish this goal we have generated transgenic mice that carry constyitutively activated forms of the Akt and PI-3f kinase under the transcriptional control of the mouse mammary tumor vims (MMTV) promoter/enhancer. To this end we thus far derived 11 independent transgenic lines carrying the MMTV/activated Akt strains and 4 independent lines expressing the MMTV/activated PI-3f kinase. Expression amalyses of these strainshas revealed that 3 of 11 MMTV/activated Akt mice express the activated Akt transgene in the mammary epithelium whereas we have not yet detected transgene expression in any of the MMTV/PI-3f kinase strains. Although expression of Akt-DD interferes with normal mammary gland involution, mammary tumors were not observed in these strains. To explore the potential role of Akt in mammary tumor progression, mice co-expressing AktnDD and a mutant form of Polyomavirus middle T (PyV mT) antigen de-coupled from PI3KIAkt signaling pathways 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 in mammary epithelium expressing the mutant form of PyV mT. Taken together these observations indicate that activation of Akt can contribute to tumoc
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2000
- Accession Number
- ADA389510
Entities
People
- William Muller
Organizations
- McMaster University