Tumor development and progression of experimental skin squamous cell carcinoma (SCC) induced by chemical carcinogens and promoters are a consequence of genetic lesions including not only abnormalities of known oncogenes and tumor suppressor genes but also the overexpression of cell cycle related genes (CCRG) such as cyclin D1. The fact that the principal investigator is ahead of everyone else in this field guarantees that definitive progress will be made during the proposed funding period. The present proposal relates to the study of a group of human SCC's of the oral cavity that have a strong etiological linkage with alcohol and tobacco consumption and also harbor similar abnormalities in cyclin D1. The hypothesis is that increased expression of multiple G1 cyclins and their respective Cdk's can be used as markers of poor prognosis in human head and neck SCC's, and that this occurs in most cases without gene amplification via either increased rates of transcription, increased message stability, or post-translational mechanisms such as increased protein half-life. Experiments are designed to: a) detect changes in G1/S cyclins, and their respective Cdk's in oral cancer and its precursors; b) utilize an extensive epidemiological data bank to which the principal investigator has access to evaluate the role of CCRG abnormalities in oral cancer as a function of tobacco-alcohol consumption as well as dietary habits and family-clinical history; c) confirm in a large series of human lesions that CCRG overexpression could be used as a marker of tumor progression and poor prognosis; d) determine which component of the invasive/metastatic cascade is implicated in tumor progression; and e) investigate in selected SCC cell lines which CCRGs are most significant in inducing enhancement of the malignant phenotype, and which are the basic mechanisms behind the overexpression of CCRGs in SCC cells.
