Centrosome Defects, Genetic Instability and Prostate Cancer

Centrosomes are essential organelles that control mitotic spindle organization, chromosome segregation, cell shape and cell polarity--all features of epithelial gland integrity. In the studies supported by this grant, we (and another group) discovered that centrosomes were structurally and numerically abnormal in nearly all malignant human tumors. Moreover, artificial induction of centrosome defects--by elevating the levels of a single centrosome protein called pericentrin--caused cellular disorganization and genomic instability in nontumor cells. Examination of prostate tumor tissues showed that pericentrin levels were elevated and the levels increased during tumor progression. We consistently found that cells with elevated pericentrin levels had centrosome defects and genomic instability. Finally, centrosome defects were detected in a percentage of precursor lesions of prostate carcinoma (approximately equal 20% of PIN lesions) together with genetic instability. Taken together, these results suggest that centrosome defects and elevated pericentrin levels contribute to rather than result from the tumorigenic process. Centrosome defects may thus prove to be a prognostic indicator of aggressive disease.
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