Centrosome Amplification in Human Breast Cancer

描述（申请人提供）：恶性乳腺肿瘤的细胞表现出中心体缺陷，包括中心粒数量过多、微管成核能力增加和中心体蛋白质的不适当磷酸化，这种情况称为“中心体扩增”中心体扩增导致多极有丝分裂和随后的染色体不稳定性，因此，是癌症发展中出现非整倍性和表型变异的一种机制。我们认为中心体扩增是乳腺癌发展的早期事件，中心体扩增可能通过几种替代机制之一产生。我们建议在乳腺肿瘤的发展过程中的中心体扩增的起源的特点。我们将测试的假设，ER和生长因子信号是机械耦合到中心粒分离和中心体复制。最后，我们将通过实验破坏正常乳腺和肿瘤细胞系的细胞周期进程，以验证G1/S和G2/M细胞周期检查点与中心体复制机械耦合以及这种联系在乳腺肿瘤发生过程中变得不耦合的假设。中心体行为的研究对于我们理解恶性肿瘤的起源具有重要意义，并可能为干预或预防乳腺癌的发展提供新的靶点。

DESCRIPTION (provided by applicant): Cells of malignant breast tumors exhibit centrosome defects including an excess number of centrioles, increased microtubule nucleation capacity, and inappropriate phosphorylation of centrosomal proteins, a condition termed 'centrosome amplification Centrosome amplification leads to multipolar mitosis and consequent chromosomal instability, and therefore, is one mechanism by which aneuploidy and phenotypic variability arise in the development of cancer. We propose that centrosome amplification is an early event in the development of breast cancer, and that amplified centrosomes may arise through one of several alternative mechanisms. We propose to characterize the origin of centrosome amplification during the development of breast tumors. We will test the hypothesis that ER and growth factor signaling are mechanistically coupled to centriole separation and centrosome duplication. And finally, we will experimentally disrupt cell cycle progression in normal breast and tumor-derived cell lines to test the hypothesis that the G 1/S and G2/M cell cycle checkpoints are mechanistically coupled to centrosome duplication and that this linkage becomes uncoupled during mammary tumorigenesis. The study of centrosome behavior is of fundamental importance to our understanding of the origin of malignant tumors and may reveal new targets for intervention or prevention of the development of breast cancer.