Centrosome Defects, Genetic Instability and Breast Cancer Progression

Abstract : Centrosomes are cellular organelles involved in the organization of mitotic spindles and thus, in the segregation of chromosomes during mitosis. When defective, centrosomes may contribute to chromosome missegregation and aneuploidy in human cancers (Pihan et al., 1998; Doxsey, 1998). In this proposal we investigate whether centrosome-defects: 1. Are an intrinsic feature of clinically aggressive prostate carcinoma, 2. Provide a prognostic marker for aggressive prostate cancer and 3. Contribute to prostate tumorigenesis. To achieve these goals, we recently developed a high-resolution microscopic method and a quantitative assay to monitor centrosome defects in archival prostate cancer tissue. We used these approaches to demonstrate that both centrosome structure and cellular levels of the centrosome protein pericentrin, are abnormal in most malignant prostate tumors (Pihan et al., 1998 and Appendix). We have also initiated construction of permanent cell lines expressing pericentrin and produced cell lines expressing GFP-histones (to label chromosomes). These cell lines will be used to study the mechanism of chromosome segregation/aneuploidy in tumor cells. Perhaps most exciting are our recent findings showing that: 1. Prostate cancer precursor lesions have centrosome defects and that 2. Overexpression of pericentrin causes mitotic spindle abnormalities, chromosomal instability and aneuploidy in normal cells. Taken together, these results suggest that pericentrin overexpression and centrosome defects may contribute to aneuploidy, a condition that is commonly observed during development and progression of malignant tumors. In future studies, we hope to answer these questions.