WAP-TAg transgenic mice and the study of dysregulated cell survival, proliferation, and mutation during breast carcinogenesis

Understanding the process of carcinogenesis is key to developing therapies which might interrupt or reverse tumor onset and progression. Cell growth a nd death signals are dependent not only upon molecular mechanisms within a cell but also upon external stimuli such as hormones, cell-cell signaling, and extracellular matrix, Mouse models can be used to dissect these complex processes, to identify key signaling pathways operating at different stage s of tumorigenesis, and to test the strength of specific interventions. In the WAP-TAg mouse model, carcinogenesis is initiated by expression of the S imian Virus 40 T antigen (TAg), TAg expression is triggered by hormonal sti mulation, either during estrus or pregnancy. Breast adenocarcinomas (rangin g from well to poorly differentiated) develop in 100% of the female mice by approximately 8-9 months of age, Three distinct stages of tumorigenesis ar e easily identified: an initial proliferation, hyperplasia; and adenocarcin oma. The mean time to first palpable tumor in mice which undergo at least o ne pregnancy is 6 months. The tumorigenic process is marked by a competitio n between proliferation and apoptosis and is characterized by cellular acqu isition of genetic mutations and increased stromal fibrosis. Protein levels of cell cycle control genes cyclin D1, cdk2, and E2F-1 are increased in th ese adenocarcinomas. c-Fos protein levels are slightly increased in these c ancers, while c-Jun levels do not change. Hormonal exposure alters progress ion, Estrogen plays a role during the early stages of oncogenesis although the growth of the resulting adenocarcinomas is estrogen-independent. Transi ent hormonal stimulation by glucocorticoids that temporarily increases the rate of cell proliferation results in tetraploidy, premature appearance of irreversible hyperplasia, and early tumor development. Tumor appearance als o can be accelerated through over expression of the cell survival protein, Bcl-2, Bcl-2 over expression not only reduces apoptosis during the initial proliferative process but also decreases the total rate of cell proliferati on. This block in cell proliferation is lost selectively as the cells trans ition to adenocarcinoma, The WAP-TAg model can be utilized to investigate h ow the basic processes of cell proliferation, apoptosis, DNA mutation, and DNA repair are modified by external and internal signals during mammary onc ogenesis.