In the last few years our laboratory has provided evidence suggesting a possible role of chromosomal numerical abnormalities (aneuploidy) in the progression of chemically induced skin tumors. Furthermore, specific non-random chromosomal alterations were identified and a temporal relationship between chromosomal abnormalities and different stages of tumor development were established. The purpose of the present proposal will be to confirm and expand those findings, to provide evidence that chromosomal abnormalities are a casual element and not an epiphenomena of tumor progression and to investigate possible mechanisms by which aneuploidy may play a role in carcinogenesis.
The specific aims of this project will be: 1) to investigate whether drugs that induce chromosomal nondisjunction can modify the rate of tumor progression in vivo and in vitro. Since our current hypothesis states that tumor progression occurs as a result of random nondisjunctions followed by the selection of cells with specific trisomies, we speculate that by increasing the frequency of nondisjunction we will be able to modify the rate of tumor conversion. 2) to define if the Trisomy 7 (Ts 7) occur by duplication of the chromosome that carries the activated Ha-ras or if the Ts 7 occurs randomly in any of the two chromosomes 7 (normal or mutated). 3) to study if the sequential trisomies of chromosomes 6 or 7 found in papillomas can be correlated with changes of expression of critical genes located in these chromosomes (Ki-ras and raf-1 for chromosome 6 and Ha- ras for chromosome 7). 4) to define more precisely the nature of the specific trisomies in mouse carcinogenesis by using mouse sticks with appropriate cytogenetic markers: (i.e., Robertsonian and balanced translocations). The purpose of the experiments using specific markers will be a) to determine the relevant regions of chromosomes 6 and 7 responsible for tumor progression, b) to analyze cytogenetically tumors in F1 crosses between SENCAR and stocks bearing cytogenetic markers, c) to investigate if a preferential loss of the copy of chromosome 7 carrying the non-mutated Ha-ras allele is required for carcinoma development.
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