The experiments described in this proposal are aimed at understanding oncogenesis by polyomavirus in infections of its natural host, the mouse. The focus is on the induction of mammary tumors, as a model for human breast tumors. The mammary gland is a member of a group of organs (which also include the bone and the skin) which comprise the targets for the majority of the polyoma tumors. This group consists of a subset of all the organs that the virus can infect, and represents the only organs in which replication can occur to substantial level in adult animals. The hypothesis to be tested is that in this group of organs, viral replication is controlled by cis-acting sequences, which are the binding sites for the mouse homolog of the transcription factors AP1 and c-ets factors; that middle T, the Py viral oncogene, activates these factors, and that this activation plays a major role in the induction of tumors.
The specific aims are to map the cis-acting sequences that control replication and tumorigenesis in the mammary gland, to test for the activation of the AP1/c-ets, and to define the domains of middle T which are responsible for the activation of these factors and for tumorigenesis. These experiments are highly relevant to the understanding of human breast cancer, a tumor whose incidence is still rising and for which very few relevant model systems are available. The advantage of studying Py oncogenesis are many: 1. the tumors are ductal adenocarcinoma, similar to their human counterpart; 2. the induction of the tumors has an estrogen sensitive phase; 3. the tumors appear very rapidly, in multiple numbers in virtually all infected animals; 4. various distinct phases of the neoplastic process are apparent: hyperplasia, dysplasia, frank neoplasia and overt tumors. Although the human tumors are evidently not of viral etiology, deregulation of the same pathway by other agents may be implicated, as it is plausible that the major fractions of organ specific tumors involve similar pathways of deregulation. Furthermore, the AP1 and probably c-ets as well gene products play important roles in many aspects of cell growth control. Further understanding on the regulation of these proteins is central to understanding multiples aspects of carcinogenesis. Furthermore, the focus of the grant on replication and persistence has an interest that extends to other persistent viral diseases with or without associated cancers (for example papilloma and hepatitis infections).
| Fluck, Michele M; Schaffhausen, Brian S (2009) Lessons in signaling and tumorigenesis from polyomavirus middle T antigen. Microbiol Mol Biol Rev 73:542-63, Table of Contents |
| Wirth, J J; Chen, L; Fluck, M M (2000) Systemic polyomavirus genome increase and dissemination of capsid-defective genomes in mammary gland tumor-bearing mice. J Virol 74:6975-83 |
| Wirth, J J; Martin, L G; Fluck, M M (1997) Oncogenesis of mammary glands, skin, and bones by polyomavirus correlates with viral persistence and prolonged genome replication potential. J Virol 71:1072-8 |
| Fluck, M M; Haslam, S Z (1996) Mammary tumors induced by polyomavirus. Breast Cancer Res Treat 39:45-56 |
| Rondinelli, R H; Haslam, S Z; Fluck, M M (1995) The role of ovarian hormones, age and mammary gland development in polyomavirus mammary tumorigenesis. Oncogene 11:1817-27 |
