CENTROSOME HYPERTROPHY IN HUMAN BREAST TUMORS

描述：（改编自研究者摘要）中心体 在维持细胞极性和进展通过 细胞周期通过确定的数量，极性，和组织， 间期和有丝分裂纺锤体微管。 中心体缺陷 组织和功能对细胞有深远的影响，包括 细胞极性丧失和染色体分离 在许多癌细胞中观察到的异常。 细胞周期检查点调控 中心体复制被认为是在p53的影响下进行的。 在初步研究中，他们仔细检查了 在人类乳腺肿瘤中的中心体，以确定中心体异常 发生在这些细胞中。 初步研究显示， 乳腺肿瘤中心体几种性质的特征性变化 细胞包括：关键中心体蛋白的过度积累， 多余的中心粒和不适当的磷酸化状态， 中心体蛋白 此外，他们还开发了一种新型微管， 成核测定以评估乳腺肿瘤细胞中心体功能。 他们的 初步研究进一步表明，乳腺肿瘤细胞显示， 特异性功能性中心体异常，其特征为 大量的MTOC使大的微管星状体成核。 因此， 本研究拟：1）确定中心体的细胞周期调控机制 在正常乳腺上皮和乳腺肿瘤衍生细胞系中的复制， 2)以确定改变之间的功能关系， 中心体结构和细胞极性的丧失， 在乳腺癌中观察到的染色体分离异常，以及3） 系统和定量地表征分子和结构 人乳腺组织中的中心体异常标记物， 增殖性和非增殖性纤维囊性疾病，LCIS，DCIS，和 浸润性导管癌和小叶癌。 拟议的研究代表了一种新的方法来理解 细胞极性的丧失和增加的倾向 在许多癌细胞中观察到的染色体分离异常， 这些研究可能提供新的靶标，可用于开发新的 临床干预。

DESCRIPTION: (adapted from the investigator's abstract) 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.