The theme of this program project is the investigation of selected cellular and biochemical events which may be instrumental in the malignant transformation of normal human urothelium into urothelial carcinoma. The processes we shall study- chromosomal/genetic loses in multistep transformation in vitro, carcinogen activity by target tissue, and target cell responsiveness to an ubiquitous growth factor - all have strong evidence linking them to fundamental events in urothelial cell tumorigenesis. Overall Objective: To elucidate how normal cellular components and events become altered and/or """"""""take advantage"""""""" of their unique environment, to contribute to the expression of the transformed phenotype.
Specific Aims : To test the following hypotheses: *Chromosomal/genetic losses correlate with tumorigenic transformation in vitro and neoplastic progression of human uroepithelial cells. *N-acetylases and deacetylases play a determinate role in susceptibility to bladder cancer. *Enzymatic activation and/or inactivation of arylamine bladder carcinogens by human urothelium occurs, and influences an individual's susceptibility for developing bladder cancer. *Alterations in post-ligand binding events occur in transformed transitional epithelial cells which enable them, but not their normal counterparts, to be stimulated by a mitogen to which they are both continually exposed - epidermal growth factor. These investigations will provide insights into the processes of neoplastic development and growth, and may yield information of importance for clinical classification, early detection, prognosis, prevention and treatment of urothelial cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA051987-03
Application #
3094473
Study Section
Special Emphasis Panel (SRC (D2))
Project Start
1990-04-15
Project End
1995-02-28
Budget Start
1992-03-10
Budget End
1993-02-28
Support Year
3
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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Hatcher, J F; Swaminathan, S (1995) Detection of deoxyadenosine-4-aminobiphenyl adduct in DNA of human uroepithelial cells treated with N-hydroxy-4-aminobiphenyl following nuclease P1 enrichment and 32P-postlabeling analysis. Carcinogenesis 16:295-301
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Hatcher, J F; Rao, K P; Swaminathan, S (1993) Mutagenic activation of 4-aminobiphenyl and its N-hydroxy derivatives by microsomes from cultured human uroepithelial cells. Mutagenesis 8:113-20
Kao, C; Huang, J; Wu, S Q et al. (1993) Role of SV40 T antigen binding to pRB and p53 in multistep transformation in vitro of human uroepithelial cells. Carcinogenesis 14:2297-302
Kao, C; Hauser, P; Reznikoff, W S et al. (1993) Simian virus 40 (SV40) T-antigen mutations in tumorigenic transformation of SV40-immortalized human uroepithelial cells. J Virol 67:1987-95

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