Role of SV40 in Salivary Gland Tumorigenesis

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DESCRIPTION: (provided by applicant) Malignant salivary gland tumors are highly heterogeneous. The varied biologic behavior, infrequency and high risk of recurrence makes the clinical management of these tumors challenging. The long term objectives of this project are: 1) to understand early molecular changes occurring in salivary gland tumorigenesis; 2) to determine the role of simian virus 40 (SV40) small t antigen (t-ag) in salivary gland tumorigenesis; and 3) to create an animal model which can be utilized to examine the role of glycosyltransferase enzymes in salivary gland tumorigenesis and metastasis. A number of transgenic mouse models in which salivary gland tumors form have been used to analyze molecular changes in malignant tissues. Overexpression of either the polyoma middle T antigen (PyVmT) or the simian virus 40 (SV40) large T antigen in murine salivary glands results in hyperplasia and tumor formation. The specific aims of this project are: 1) To examine molecular markers of tumorigenesis in hyperplastic lesions of MMTV/PyVmT mice. A combination of microscopic, morphometric and immunohistochemical analysis will be carried out to obtain information about transgene expression, epithelial cell proliferation and differentiation, microvascular density, glycosylation changes and stromal alterations in the glands. 2) To investigate the role of SV40 t-ag in salivary gland tumorigenesis. Single copy targeting vectors containing the SV40 Tt-ag or T-ag alone under the control of the parotid secretory protein promoter will be knocked in to the mouse germline by electroporation into embryonic stem (ES) cells. ES cells positive for the homologous recombination event will be injected into blastocysts to generate gene targeted mice. The mice will be backcrossed into the C57Bl/6 background and examined for t-ag and T-ag expression using fluorescent protein reporters. Analysis of molecular changes occurring during salivary gland tumorigenesis may lead to the development of therapeutic agents for the treatment of malignant disease.