Centrosome amplification drives chromosomal instability in breast tumor development
Centrosome amplification drives chromosomal instability in breast tumor development
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DOI：
10.1073/pnas.032479999
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发表时间：
2002-02-19
影响因子：
11.1
通讯作者：
Salisbury, JL
中科院分区：
文献类型：
--
作者：
Lingle, WL;Barrett, SL;Salisbury, JL
早期对浸润性乳腺肿瘤的研究表明，60-80%为非整倍体，约80%表现为中心体扩增。在这项研究中，我们研究了人类乳腺肿瘤中中心体扩增与非整倍体、染色体不稳定性、p53突变和分化丧失的关系。用着丝粒探针对3、7、17号染色体进行荧光原位杂交，分析了20例浸润性乳腺肿瘤和7例正常乳腺组织。我们分析了这些肿瘤的非整倍体和不稳定核型，由染色体不稳定性决定。然后测试结果与中心体扩增的三个指标的相关性：中心体大小、中心体数量和中心体微管成核能力。中心体大小和中心体数目均与非整倍性和染色体不稳定性呈显著正线性相关。微管成核能力没有这种相关性，但确实与组织分化的丧失显著相关。在原位导管癌中检测到中心体扩增，表明中心体扩增是这些病变的早期事件。中心体扩增和染色体不稳定独立于p53突变发生，而p53突变与中心体微管成核能力的显著增加有关。总之，这些结果表明，中心体扩增的独立方面与染色体不稳定和组织分化丧失相关，并可能参与肿瘤的发生和进展。这些结果进一步表明，中心体扩增的某些方面可能具有临床诊断和/或预后价值，中心体可能是癌症治疗的潜在靶点。
Earlier studies of invasive breast tumors have shown that 60-80% are aneuploid and approximate to80% exhibit amplified centrosomes. In this study, we investigated the relationship of centrosome amplification with aneuploidy, chromosomal instability, p53 mutation, and loss of differentiation in human breast tumors. Twenty invasive breast tumors and seven normal breast tissues were analyzed by fluorescence in situ hybridization with centromeric probes to chromosomes 3, 7, and 17. We analyzed these tumors for both aneuploidy and unstable karyotypes as determined by chromosomal instability. The results were then tested for correlation with three measures of centrosome amplification: centrosome size, centrosome number, and centrosome microtubule nucleation capacity. Centrosome size and centrosome number both showed a positive, significant, linear correlation with aneuploidy and chromosomal instability. Microtubule nucleation capacity showed no such correlation, but did correlate significantly with loss of tissue differentiation. Centrosome amplification was detected in in situ ductal carcinomas, suggesting that centrosome amplification is an early event in these lesions. Centrosome amplification and chromosomal instability occurred independently of p53 mutation, whereas p53 mutation was associated with a significant increase in centrosome microtubule nucleation capacity. Together, these results demonstrate that independent aspects of centrosome amplification correlate with chromosomal instability and loss of tissue differentiation and may be involved in tumor development and progression. These results further suggest that aspects of centrosome amplification may have clinical diagnostic and/or prognostic value and that the centrosome may be a potential target for cancer therapy.