Centrosome amplification induces high grade features and is prognostic of worse outcomes in breast cancer.
Centrosome amplification induces high grade features and is prognostic of worse outcomes in breast cancer.
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DOI：
10.1186/s12885-016-2083-x
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发表时间：
2016-01-29
期刊：
影响因子：
3.8
通讯作者：
Burkard ME
中科院分区：
文献类型：
--
作者：
Denu RA;Zasadil LM;Kanugh C;Laffin J;Weaver BA;Burkard ME
中心体扩增（CA）在几乎所有类型的人类癌症中都有报道，并且与有害的临床因素如较高的级别和阶段有关。然而，以前的报告没有显示CA如何影响乳腺癌的细胞分化和临床结果。我们通过免疫荧光分析了中心体，并将其与6-染色体FISH评估的倍性和染色体不稳定性（CIN）进行了比较，该队列包括362例乳腺癌，中位临床随访时间为8.4年。中心体通过免疫荧光法使用针对中心粒周围物质（PCM;中心粒周围蛋白）和中心粒（多聚谷氨酰化微管蛋白）的抗体来识别。CA实验诱导细胞培养物中的polo样激酶4（PLK 4）的过度表达。CA与全因和乳腺癌特异性总生存率和无复发生存率降低相关。CA与高风险亚型（例如三阴性）和较高的分期和分级密切相关，CA的预后性质在很大程度上可以通过这些因素来解释。CA和高肿瘤倍性之间的强相关性表明染色体和中心体加倍经常同时发生。CA被认为是一种通过异常有丝分裂细胞分裂诱导CIN的方法;与此一致，我们观察到乳腺癌中CA和CIN之间的强相关性。然而，一些CA肿瘤的CIN水平较低，表明保护机制在起作用，例如有丝分裂期间的中心体聚集。有趣的是，一些高危肿瘤具有更多的无中心粒中心体，这表明PCM片段化是CA的另一种机制。在两个非转化的人类细胞系（MCF 10A和RPE）中CA的体外诱导表明，CA诱导去分化的细胞状态和高级别恶性肿瘤的特征，支持CA内在地导致高级别肿瘤的想法。CA与乳腺癌的有害临床因素和结果相关。细胞倍增事件是癌症中CA的最普遍原因，尽管PCM碎片可能是次要原因。CA促进高风险乳腺癌的部分原因是诱导高级别的功能。这些发现强调了中心体畸变在人类乳腺癌生物学中的重要性。本文的在线版本（doi：10.1186/s12885-016-2083-x）包含补充材料，可供授权用户使用。
Centrosome amplification (CA) has been reported in nearly all types of human cancer and is associated with deleterious clinical factors such as higher grade and stage. However, previous reports have not shown how CA affects cellular differentiation and clinical outcomes in breast cancer. We analyzed centrosomes by immunofluorescence and compared to ploidy and chromosomal instability (CIN) as assessed by 6-chromosome FISH in a cohort of 362 breast cancers with median clinical follow-up of 8.4 years. Centrosomes were recognized by immunofluorescence using antibodies for pericentriolar material (PCM; pericentrin) and centrioles (polyglutamylated tubulin). CA was experimentally induced in cell culture by overexpression of polo-like kinase 4 (PLK4). CA is associated with reduced all-cause and breast cancer-specific overall survival and recurrence-free survival. CA correlates strongly with high-risk subtypes (e.g. triple negative) and higher stage and grade, and the prognostic nature of CA can be explained largely by these factors. A strong correlation between CA and high tumor ploidy demonstrates that chromosome and centrosome doubling often occur in concert. CA is proposed to be a method of inducing CIN via aberrant mitotic cell divisions; consonant with this, we observed a strong correlation between CA and CIN in breast cancers. However, some CA tumors had low levels of CIN, indicating that protective mechanisms are at play, such as centrosome clustering during mitosis. Intriguingly, some high-risk tumors have more acentriolar centrosomes, suggesting PCM fragmentation as another mechanism of CA. In vitro induction of CA in two non-transformed human cell lines (MCF10A and RPE) demonstrated that CA induces a de-differentiated cellular state and features of high-grade malignancy, supporting the idea that CA intrinsically causes high-grade tumors. CA is associated with deleterious clinical factors and outcomes in breast cancer. Cell doubling events are the most prevalent causes of CA in cancer, although PCM fragmentation may be a secondary cause. CA promotes high-risk breast cancer in part by inducing high-grade features. These findings highlight the importance of centrosome aberrations in the biology of human breast cancer. The online version of this article (doi:10.1186/s12885-016-2083-x) contains supplementary material, which is available to authorized users.