The investigator's observation that the me PTP1C spontaneous """"""""knockout"""""""" mouse has an unusually high incidence of breast cancer, and the mammary tumor cell lines they have derived from this strain, provide a novel system for delineating the role of the putative tumor suppressor, PTP1C, in the initiation and progression of breast cancer. By introducing PTP1C into human breast cancer cell lines and determining the effects of PTP1C overexpression on growth in vitro and in vivo, they will extend the data derived in this murine model system to the analysis of PTP1C relevance to human breast cancer. It is hypothesized that PTP1C functions as a tumor suppressor in mammary tumorigenesis. Over and under expression of wild type and dominant negative forms of PTP1C will be utilized to determine the role of the putative PTP1C tumor suppressor in the initiation and progression of breast cancer in human and murine model systems. The will localize PTP1C in the signaling cascades activated in breast epithelium. Hypotheses generated from these in vitro studies will be tested by crossing PTP1C deficient me mice with existing transgenic and """"""""knockout"""""""" mice to further characterize the role of PTP1C in preventing mammary tumorigenesis in vivo. The investigators recently obtained preliminary data linking loss of function mutation in the PTP1C gene to expression of the murine motheaten (me) syndrome rendered this spontaneous knock out mouse a valuable model for the study of the role of PTPs in mammary tumorigenesis. They propose to utilize this PTP1C deficient """"""""me"""""""" mice to test their hypothesis that PTPs act as a tumor suppressor in breast epithelium in preventing the development of breast cancer. During the initial studies of the investigators' experiment, they have observed that the loss of PTP1C function contributes to the development of breast tumors in """"""""me"""""""" mice. The data also show that overexpression PTP1C in human breast derived tumors decreases proliferation, increases differentiation, and in nude mice decreases tumor formation. All these results demonstrate that PTP1C may function as a tumor suppressor by counteracting cellular events involving tyrosine phosphorylation in the development of mammary cancer. Based on these preliminary results, the investigators proposed to introduce PTP1C gene into human breast cancer cell lines and determine the effects of PTP1C overexpression on growth in vitro and in vivo. In addition, the investigators would like to extend their observation utilizing """"""""me"""""""" model system for the analysis of PTP1C and its relevance to human breast cancer. Further investigation of the role of PTP1C is likely to improve understanding of mammary tumorigenesis, and it may eventually lead to new approaches for the diagnosis prevention or management of this devastating tumor. The investigators also propose to develop a strategy whereby the expression of PTP1C can be regulated or suppressed in order to demonstrate the initiation and progression of breast cancer in human and murine model system.
| Cuevas, B; Lu, Y; Watt, S et al. (1999) SHP-1 regulates Lck-induced phosphatidylinositol 3-kinase phosphorylation and activity. J Biol Chem 274:27583-9 |
| Lu, Y; Lin, Y Z; LaPushin, R et al. (1999) The PTEN/MMAC1/TEP tumor suppressor gene decreases cell growth and induces apoptosis and anoikis in breast cancer cells. Oncogene 18:7034-45 |
| Davies, M A; Lu, Y; Sano, T et al. (1998) Adenoviral transgene expression of MMAC/PTEN in human glioma cells inhibits Akt activation and induces anoikis. Cancer Res 58:5285-90 |
