Transgenic mice are powerful tools to study normal and abnormal cellular processes. A transgenic mouse strain with a high incidence of salivary gland tumors was generated by Drs. Bernd Grioner and Anne-Catherine Andres (LICR, Switzerland) by germline introduction of an activated Ha-ras oncogene. The initial intent was to target oncogene expression to the mammary gland. Thus, the activated human Ha-ras oncogene was subjected to the regulation of promoter sequences of the murine whey acidic protein (WAP) gene, a mammary gland-specific product. One male mouse transmitted the hybrid WAP-Ha-ras sequences only to the male progeny suggesting integration into the Y chromosome. Unexpectedly, this rare event resulted in WAP-Ha-ras expression only in the salivary glands of the male progeny who also developed salivary gland tumors within 8-15 months of age. The tumors exhibited enhanced expression of the WPA-Ha-ras sequences. The long range goal of the applicant's laboratory is to establish the mechanisms whereby activated oncogenes with different functions may interfere with normal and abnormal salivary epithelial cell transitions. The transgenic mouse model described above presented a unique opportunity for our salivary gland studies. A collaborative effort was initiated with Dr. Bernd Groner and, in 1988, a transgenic mouse colony was established here at the University of Texas DB with funds provided by the Biomedical Research Support Grant. The funding was for a limited time only. An appropriate pilot study requires at least two years of support since the mean latent period for tumor development is 12 months.
The specific aims of this pilot project are: (1) To continue the transgenic mouse colony; (2) To correlate the latency period of tumor development in individual transgenic mice with neoplastic involvement of specific salivary glands; (3) To begin characterization of transgenic salivary gland tumors with monoclonal antibodies that distinguish between different cell lineages of the mouse salivary glands; and (4) To generate cell lines from uninvolved transgenic salivary glands and from those exhibiting frank tumors. The proposed study will generate knowledge crucial to understanding the relevance of oncogene expression in the development of salivary gland tumors. Future studies will address both the effects of oncogene expression on salivary glad postnatal development and function and the definition of factors that, in addition to oncogene expression, may play a role in neoplastic progression of the salivary epithelium.
