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Prostate Cancer Models of Genomic Instability
Annual summary rept. 1 Mar 2004-28 Feb 2005
FRED HUTCHINSON CANCER RESEARCH CENTER SEATTLE WA
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Genomic instability is a common feature of human cancer, and is associated with aberrant mitosis, aneuploidy, and other chromosomal irregularities 1. Genomic instability likely arises from centrosome abnormalities that induce spindle defects, leading to imbalanced chromosomal segregation. In fact, centrosome anomalies arise in early prostate cancer and occur more frequently in high-grade cancers 2. While the molecular events of genomic instability are not fully understood, their characteristics are tightly associated with aberrant expression of proteins controlling DNA damage response and cell cycle checkpoints such as the mitotic kinase Aurora-A and -B, and checkpoint protein Bub1. Overexpression of Aurora-A and -B are overexpressed in many transformed and cancer cell lines and their levels increases as a function of tumor state in many different types of cancers 3,4. Overexpression of Aurora-A kinase induces centrosome amplification, aneuploidy, abnormal cell cycles, and transformation of p53-deficient mammalian cells 5. Inactivational mutation in Bub1, although rare, functions dominantly in some cancers and induces chromosomal instability and increase aneuploidy 6,7. In addition, recently studies have shown that inactivation of Bub1 activity is essential for SV40 large T-antigen-induced neuplastic transformation 8.
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