The centrosome functions in maintenance of cell polarity and in progression through the cell cycle by determining the number, polarity, and organization of interphase and mitotic spindle microtubules. Defects in centrosome organization and function have profound consequences for the cell, including the characteristic loss of cell polarlity and chromosomal segregation abnormalities seen in many cancer cells. Cell cycle checkpoints regulating centrosome duplication are believed to operate under the influence of p53. In preliminary studies, they have performed a careful examination of centrosomes in human breast tumors to determine if centrosome abnormalities occur in these cells. The preliminary studies have revealed striking and characteristic changes in several centrosome properties in breast tumor cells including: excess accumulation of key centrosomal proteins, supernumerary centrioles, and inappropriate phosphorylation status of centrosome proteins. In addition, they have developed a novel microtubule nucleation assay to assess breast tumor cell centrosome function. Their preliminary studies further demonstrate that breast tumor cells show specific functional centrosome abnormalities characterized by inappropriate numbers of MTOCs that nucleate large microtubule asters. They, therefore, propose to: 1) determine the cell cycle control mechanism for centrosome duplication in normal breast epithelial and breast tumor derived cell lines, 2) to determine the functional relationship between alterations in centrosome structure and the loss of cell polarity and increase in chromosomal segregation abnormalities seen in breast carcinomas, and 3) to systematically and quantitatively characterize molecular and structural markers for centrosome abnormalities in human breast tissues from proliferating and nonproliferating fibrocystic disease, LCIS, DCIS, and invasive ductal and lobular carcinomas. The proposed studies represent a novel approach to understanding the mechanism of loss of both cell polarity and the increased propensity toward chromosomal segregation abnormalities seen in many carcinoma cells, and these studies may provide new targets useful in the development of novel clinical interventions.
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