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Date of Award

2003

Degree Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

Supervisor

Dr. William J. Muller

Abstract

Activation of Akt-1 by the phosphatidylinositol 3'-OH kinase (PI3K) results in the inhibition of pro-apoptotic signals and the promotion of survival and proliferation signals. Transgenic mice expressing polyomavirus middle T antigen in the mammary epithelium rapidly develop multifocal metastatic mammary tumors whereas transgenic mice expressing a mutant middle T antigen de-coupled from the PI3K (MTY315/322F) develop extensive mammary gland hyperplasias that are highly apoptotic. Mammary tumorigenesis in this mutant strain is further associated with Akt-1 activation and overexpression of receptor tyrosine kinases (RTKs) known to activate the PI3K. To directly assess the role of Akt-1 in mammary epithelial development and tumorigenesis, we generated transgenic mice expressing constitutively active Akt-1 (HAPKB308D473D or Akt-DD). Although expression of Akt-DD interferes with normal mammary gland involution, tumors were not observed in these strains. Importantly, co-expression of Akt-DD with MTY315/322F results in phosphorylation of the FKHR transcription factor and post-transcriptional up-regulation of cyclin DI levels. In support of a broader role for Akt-1 in RTK-mediated mamary tumorigenesis, bi-transgenics carrying MMTV/Akt-DD and MMTV/activated ErbB-2 develop multifocal mammary tumors with a significatnyl shorter latency period than mice expressing activated ErbB-2 alone. The acceleration of mammary tumor progression correlated with enhanced differentiation, increased cellular proliferation, post-transcriptionally elevated Cyclin D1 levels and phosphorylation of retinoblastoma protein. Importantly, we did not observe an associated restoration of wildtype metastasis levels in either of these bi-transgenic strains and actually witnessed metastasis levels in either of these bi-transgenic strains and actually witnessed metastatic reductions in the Akt-DDxErbB-2 bi-transgenics. These observations suggest that activation of Akt-1 can contribute to tumor progression by providing an important cell survival signal and may in certain cases act to prevent metastatic progression through the promotion of a mammary differentiation program.

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