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Clinical Validation of Candidate Genes Associated with Prostate Cancer Progression in the CWR22 Model System using Tissue Microarrays¹

Cancer Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland 20892 [S. M., U. W., G. H., J. K., R. C., N. G., A. G. E., O-P. K.]; Institute of Pathology, University of Basel, Basel 4003, Switzerland [L. B., N. W., G. S.]; Laboratory of Cancer Genetics, Tampere University Hospital, 33521 Tampere, Finland [P. K.]; and Department of Pathology, National Cancer Institute, NIH, Bethesda, Maryland 20850 [W. F., M. R.]

To explore molecular mechanisms of prostate cancer progression, we applied tissue microarrays (TMAs) to analyze expression of candidate gene targets discovered by cDNA microarray analysis of the CWR22 xenograft model system. A TMA with 544 clinical specimens from different stages of disease progression was probed by mRNA in situ hybridization and protein immunohistochemistry. There was an excellent correlation (r = 0.96; n = 16) between the expression levels of the genes in the xenografts by cDNA microarray and mRNA in situ hybridization on a TMA. One of the most highly overexpressed genes in hormone-refractory CWR22R xenografts was the S100P gene. This gene, coding for a calcium signaling molecule implicated in the loss of senescence, was also significantly associated with progression in clinical tumors by TMA analysis (P < 0.001), suggesting dysregulation of this pathway in hormone-refractory and metastatic prostate cancers. Conversely, two genes that were down-regulated during tumor progression in the CWR22 model system were validated in vivo: crystallin µ (CRYM) and a LIM-domain protein LMO4 both showed significantly lower mRNA levels in hormone-refractory tumors as compared with primary tumors (P < 0.001). These results illustrate a strategy for rapid clinical validation at the mRNA and protein level of gene targets found to be differentially expressed in cDNA microarray experiments of model systems of cancer.

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