ANLN is a prognostic biomarker independent of Ki-67 and essential for cell cycle progression in primary breast cancer.
ANLN is a prognostic biomarker independent of Ki-67 and essential for cell cycle progression in primary breast cancer.
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DOI：
10.1186/s12885-016-2923-8
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发表时间：
2016-11-18
期刊：
影响因子：
3.8
通讯作者：
Pontén F
中科院分区：
文献类型：
--
作者：
Magnusson K;Gremel G;Rydén L;Pontén V;Uhlén M;Dimberg A;Jirström K;Pontén F
苯胺醛（ANLN），一种细胞质分裂所需的肌动蛋白结合蛋白，最近被认为是乳腺癌预后标志物的一部分。本研究的目的是进一步探讨ANLN作为乳腺癌单一生物标志物的预后和功能价值。ANLN蛋白表达的免疫组织化学评估在两个具有长期临床随访数据的充分表征的乳腺癌群组（n = 484）中进行，并且结果在公开可用的转录组学数据集中在mRNA水平上进一步验证。ANLN的功能相关性进行了研究，在两个乳腺癌细胞系使用RNA干扰。在两个研究队列中，乳腺肿瘤细胞中ANLN的高核分数与肿瘤大小大、组织学分级高、增殖率高、激素受体阴性肿瘤和预后差显著相关。多变量分析显示ANLN和生存率之间的关联在队列I中显著独立于年龄，并且显著独立于增殖，如通过肿瘤细胞中Ki-67表达、年龄、肿瘤大小、ER和PR状态、HER 2状态和队列II中的淋巴结状态所评估的。ANLN mRNA表达分析证实，ANLN高表达与乳腺癌患者总体生存率低显著相关。与ANLN在胞质分裂过程中的作用一致，在乳腺癌细胞系中ANLN蛋白表达的瞬时敲低导致衰老细胞的增加和细胞在细胞周期的G2/M期的积累，细胞形态改变，包括大的多核细胞。此外，ANLN siRNA敲除还导致细胞周期蛋白D1、A2和B1的表达降低。ANLN在乳腺癌细胞中的表达在细胞分裂过程中起重要作用，并且肿瘤细胞中高比例的核ANLN表达与乳腺癌患者的不良预后相关，与Ki-67、肿瘤大小、激素受体状态、HER 2状态、淋巴结状态和年龄无关。本文的在线版本（doi：10.1186/s12885-016-2923-8）包含补充材料，可供授权用户使用。
Anillin (ANLN), an actin-binding protein required for cytokinesis, has recently been presented as part of a prognostic marker panel in breast cancer. The objective of the current study was to further explore the prognostic and functional value of ANLN as a single biomarker in breast cancer. Immunohistochemical assessment of ANLN protein expression was performed in two well characterized breast cancer cohorts (n = 484) with long-term clinical follow-up data and the results were further validated at the mRNA level in a publicly available transcriptomics dataset. The functional relevance of ANLN was investigated in two breast cancer cell lines using RNA interference. High nuclear fraction of ANLN in breast tumor cells was significantly associated with large tumor size, high histological grade, high proliferation rate, hormone receptor negative tumors and poor prognosis in both examined cohorts. Multivariable analysis showed that the association between ANLN and survival was significantly independent of age in cohort I and significantly independent of proliferation, as assessed by Ki-67 expression in tumor cells, age, tumor size, ER and PR status, HER2 status and nodal status in cohort II. Analysis of ANLN mRNA expression confirmed that high expression of ANLN was significantly correlated to poor overall survival in breast cancer patients. Consistent with the role of ANLN during cytokinesis, transient knock-down of ANLN protein expression in breast cancer cell lines resulted in an increase of senescent cells and an accumulation of cells in the G2/M phase of the cell cycle with altered cell morphology including large, poly-nucleated cells. Moreover, ANLN siRNA knockdown also resulted in decreased expression of cyclins D1, A2 and B1. ANLN expression in breast cancer cells plays an important role during cell division and a high fraction of nuclear ANLN expression in tumor cells is correlated to poor prognosis in breast cancer patients, independent of Ki-67, tumor size, hormone receptor status, HER2 status, nodal status and age. The online version of this article (doi:10.1186/s12885-016-2923-8) contains supplementary material, which is available to authorized users.
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