Centrosome Amplification in Human Breast Cancer

人类乳腺癌中心体扩增

• 批准号: 6542155
• 负责人: JEFFREY L SALISBURY
• 金额: $ 27.17万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6542155
• 关键词: aneuploidy; biological signal transduction; breast neoplasms; carcinogenesis; cell cycle; cell cycle proteins; centrosome; chromosome movement; electron microscopy; estrogens; flow cytometry; fluorescent in situ hybridization; growth factor receptors; high performance liquid chromatography; human tissue; immunocytochemistry; mammary epithelium; microtubules; mitotic spindle apparatus; neoplastic growth; phosphorylation; tissue /cell culture; western blottings

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.

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，以及中心体蛋白的不适当磷酸化，一种被称为中心体放大的情况，中心体放大导致多极有丝分裂和随之而来的染色体不稳定性，因此，非整倍体和表型变异在癌症的发展中出现的机制之一。我们认为中心体扩增是乳腺癌发生发展的早期事件，并且中心体扩增可能通过几种替代机制中的一种发生。我们建议在乳腺肿瘤的发展过程中表征中心体扩增的起源。我们将检验ER和生长因子信号与中心粒分离和中心体复制是机械耦合的假设。最后，我们将在实验中干扰正常乳腺和肿瘤来源的细胞系的细胞周期进程，以检验G1/S和G2/M细胞周期检查点与中心体复制机械耦合的假设，以及这种联系在乳腺肿瘤发生过程中变得解偶联的假设。中心体行为的研究对我们理解恶性肿瘤的起源具有重要意义，并可能为乳腺癌的干预或预防提供新的靶点。