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The Consequences of Chromosomal Aneuploidy on Gene Expression Profiles in a Cell Line Model for Prostate Carcinogenesis

Urologic Oncology Branch [J. L. P., J. V., C. P., W. M. L.], Genetics Branch [H. P-N., B. M. G., T. R.], Laboratory of Pathology [A. R.], Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20817; Department of Pharmacology, Georgetown University School of Medicine, Washington, DC 20007 [J. R. P.]; and Departments of Urology [S. W. H., G. D. G., G. R. C.] and Anatomy [Y. W., G. R. C.], University of California-San Francisco, San Francisco, California 94143

Here we report the genetic characterization of immortalized prostate epithelial cells before and after conversion to tumorigenicity using molecular cytogenetics and microarray technology. We were particularly interested to analyze the consequences of acquired chromosomal aneuploidies with respect to modifications of gene expression profiles. Compared with nontumorigenic but immortalized prostate epithelium, prostate tumor cell lines showed high levels of chromosomal rearrangements that led to gains of 1p, 5, 11q, 12p, 16q, and 20q and losses of 1pter, 11p, 17, 20p, 21, 22, and Y. Of 5700 unique targets on a 6.5K cDNA microarray, 3% were subject to modification in expression levels; these included GRO-1, -2, IAP-1,- 2, MMP-9, and cyclin D1, which showed increased expression, and TRAIL, BRCA1, and CTNNA, which showed decreased expression. Thirty % of expression changes occurred in regions the genomic copy number of which remained balanced. Of the remainder, 42% of down-regulated and 51% of up-regulated genes mapped to regions present in decreased or increased genomic copy numbers, respectively. A relative gain or loss of a chromosome or chromosomal arm usually resulted in a statistically significant increase or decrease, respectively, in the average expression level of all of the genes on the chromosome. However, of these genes, very few (e.g., 5 of 101 genes on chromosome 11q), and in some instances only two genes (MMP-9 and PROCR on chromosome 20q), were overexpressed by 1.7-fold when scored individually. Cluster analysis by gene function suggests that prostate tumorigenesis in these cell line models involves alterations in gene expression that may favor invasion, prevent apoptosis, and promote growth.

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