Development and Characterization of Transgenic Mice with Mammary Gland Specific Expression of the Tumor Suppressor.

摘要

The MMAC1/PTEN/TEP1 phosphatase tumor suppressor gene contributes to the initiation and progression of breast cancer as indicated by being the cause of the Cowden's breast cancer predisposition syndrome, being mutated in a subset of breast cancers, particularly advanced breast cancer and by being decreased in breast cancers by epigenetic mechanism. Recent evidence suggests that decreased PTEN levels or function rather than complete deletion may contribute to cancer development Our preliminary date with breast cancer cells lacking MMAC1 have demonstrated that reintroduction of MMAC1 results in cell cycle arrest of apoptosis dependent on whether cells have additional viability signals provided by serum or by ligation of integrins. Deletion of MMAC1 in knockout mice results in lethality in the homozygous state and tumor development in multiple organs in a heterozygous state. Attempts to develop tissue specific knock outs of MMAC1 have failed to provide useful models due to leakiness and tumor development in other organs. To provide a model that mimics the situation in human breast cancer, we will establish tissue specific transgenic murine models with increased and decreased MMAC1 function by expression of wild type or a dominant negative MMAC1. We have: (1) generated transgene constructs for wild type MMAC1 under the MMTV promoter, as dominant negative (c/s) MMAC1 where the lipid and protein phosphatase activity is inhibited under the MMTV promoter, (2) a dominant negative MMAC I (g/e) where the lipid phosphatase activity is inhibited, (3) and the protein phosphatase is intact and a WAP MMAC1 dominant negative (c/s).