The development of human cancer proceeds in a multistep fashion involving both the loss of tumor suppressor gene function and the activation of oncogenes. While greater than one hundred oncogenes have been identified, only a modest number of tumor suppressor genes have been isolated. The discovery of most tumor suppressor genes has relied on the knowledge of their physical location on a particular chromosome; few functional assays for these genes exist. We have used the technique of microcell hybridization to map the location of tumor suppressor genes for adult and pediatric cancers. Demonstration of tumor suppression by transferring a single normal human chromosome into a human tumor cell line maps tumor suppressor gene(s) to that genetic unit. This method provides a powerful tool for identifying these genes in malignancies where extensive chromosome rearrangements and deletions mask their locale. Using this approach, we have mapped a functional tumor suppressor gene for a human squamous cell carcinoma (SCC) cell line to chromosome 11. By using a translocated chromosome T(X;11), we have localized the gene to the region between 11q13 to 11qter. We and others have also demonstrated tumor suppressor gene activity for renal cell carcinoma, lung carcinoma and cervical carcinoma on this same chromosome. Thus, our results may indicate that many types of epithelial malignancies result from the inactivation of the same tumor suppressor gene. In this grant application, we plan to localize the side of the tumor suppressor information to an approximately 1 mb region on chromosome 11. A. We have switched to the use of an in vitro raft assay which significantly decreases the time required for determination of tumor suppressor gene activity. B. We will begin to identify candidate tumor suppressor genes from this region. The availability of epidemiology data for these samples will allow us to gauge the relative importance of this tumor suppressor gene in the process of squamous cell carcinoma development. Squamous cell carcinomas appear to develop from a complex interaction of genetic, epigenetic and environmental factors. Exposure of environmental agents including alcohol, tobacco and food carcinogens may especially impact the development of oral squamous cell carcinomas. Identification and characterization of tumor suppressor genes affected by these events will allow investigators to determine the relative importance of each of them in the process of carcinogenesis. Recent reports linking other tumor suppressor genes with a genetic susceptibility to cancer emphasize the importance of these proposed studies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE012355-03
Application #
2897170
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Project Start
1997-07-15
Project End
2001-07-14
Budget Start
1999-07-15
Budget End
2001-07-14
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Hummer, B Timothy; Bartlett, Christopher; Henry, Erin et al. (2003) Expression of Smad4 in the FaDu cell line partially restores TGF-beta growth inhibition but is not sufficient to regulate fibronectin expression or suppress tumorigenicity. J Cell Physiol 194:289-302
Padalecki, S S; Weldon, K S; Reveles, X T et al. (2003) Chromosome 18 suppresses prostate cancer metastases. Urol Oncol 21:366-73
Reisman, David N; Strobeck, Matthew W; Betz, Bryan L et al. (2002) Concomitant down-regulation of BRM and BRG1 in human tumor cell lines: differential effects on RB-mediated growth arrest vs CD44 expression. Oncogene 21:1196-207
Strobeck, Matthew W; Reisman, David N; Gunawardena, Ranjaka W et al. (2002) Compensation of BRG-1 function by Brm: insight into the role of the core SWI-SNF subunits in retinoblastoma tumor suppressor signaling. J Biol Chem 277:4782-9
Strobeck, M W; DeCristofaro, M F; Banine, F et al. (2001) The BRG-1 subunit of the SWI/SNF complex regulates CD44 expression. J Biol Chem 276:9273-8
Merrihew, R V; Cruickshank, R D; Conway, K et al. (2000) Altered response of a human squamous cell carcinoma cell line to 1, 25-dihydroxyvitamin D(3) after transfer of a normal chromosome 11. Exp Cell Res 259:191-203