Amplification and high-level expression of heat shock protein 90 marks aggressive phenotypes of human epidermal growth factor receptor 2 negative breast cancer.
Amplification and high-level expression of heat shock protein 90 marks aggressive phenotypes of human epidermal growth factor receptor 2 negative breast cancer.
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DOI：
10.1186/bcr3168
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发表时间：
2012-04-17
期刊：
影响因子：
--
通讯作者：
Lyerly HK
中科院分区：
文献类型：
--
作者：
Cheng Q;Chang JT;Geradts J;Neckers LM;Haystead T;Spector NL;Lyerly HK
尽管人类表皮生长因子受体 2 (HER2) 阳性或雌激素受体 (ER) 阳性乳腺癌采用经过临床验证的抗 HER2 或抗雌激素疗法进行治疗，但相当一部分乳腺癌患者出现了对这些疗法的内在耐药性和获得性耐药性，因此需要新的疗法。识别其他分子因素，特别是那些以攻击行为和不良预后为特征的分子因素，可以优先考虑干预机会，以改善乳腺癌的诊断和治疗。我们收集了来自 23 个数据集的 4,010 个乳腺肿瘤基因表达数据，这些数据已发布在国家生物技术信息中心 (NCBI) 基因表达综合 (GEO) 数据库上。我们使用 Cox 回归生存分析进行了基因组规模的生存分析，并使用 Kaplan-Meier 估计生存和 Cox 比例风险回归生存分析进行了验证。我们使用从癌症基因组图谱 (TCGA) 获得的 481 个乳腺癌样本对染色体改变进行了基因组规模分析，从中可以获得组合表达和拷贝数数据。我们使用方差分析（ANOVA）评估了体细胞拷贝数改变与基因表达之间的相关性。每种热休克蛋白 (HSP) 90 亚型以及 HSP 转录因子 1 (HSF1) 的表达增加与不同亚型乳腺癌的不良预后相关。 HSP90AA1 和 HSP90AB1（两种细胞质 HSP90 亚型）的高水平表达是由染色体编码区扩增驱动的，分别是导致三阴性（TNBC）和 HER2-/ER+ 亚型患者死于乳腺癌的独立因素。此外，HSF1 的扩增与乳腺癌细胞中较高的 HSP90AA1 和 HSP90AB1 mRNA 表达相关，而这两个基因没有扩增。 HSP90AA1、HSP90AB1 和 HSF1 扩增的集合定义了 HSP90 基因表达上调的乳腺癌亚群，并且 HSP90 表达上调独立增加了 TNBC 复发风险和 HER2-/ER+ 乳腺癌不良预后。 HSP90 mRNA 表达上调代表基因组脆弱性的综合作用，使 HER2 阴性乳腺癌更具侵袭性，导致预后不良。通过上调的 HSP90 来靶向乳腺癌可能会提高该疾病的临床干预效果。
Although human epidermal growth factor receptor 2 (HER2) positive or estrogen receptor (ER) positive breast cancers are treated with clinically validated anti-HER2 or anti-estrogen therapies, intrinsic and acquired resistance to these therapies appears in a substantial proportion of breast cancer patients and new therapies are needed. Identification of additional molecular factors, especially those characterized by aggressive behavior and poor prognosis, could prioritize interventional opportunities to improve the diagnosis and treatment of breast cancer. We compiled a collection of 4,010 breast tumor gene expression data derived from 23 datasets that have been posted on the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database. We performed a genome-scale survival analysis using Cox-regression survival analyses, and validated using Kaplan-Meier Estimates survival and Cox Proportional-Hazards Regression survival analyses. We conducted a genome-scale analysis of chromosome alteration using 481 breast cancer samples obtained from The Cancer Genome Atlas (TCGA), from which combined expression and copy number data were available. We assessed the correlation between somatic copy number alterations and gene expression using analysis of variance (ANOVA). Increased expression of each of the heat shock protein (HSP) 90 isoforms, as well as HSP transcriptional factor 1 (HSF1), was correlated with poor prognosis in different subtypes of breast cancer. High-level expression of HSP90AA1 and HSP90AB1, two cytoplasmic HSP90 isoforms, was driven by chromosome coding region amplifications and were independent factors that led to death from breast cancer among patients with triple-negative (TNBC) and HER2-/ER+ subtypes, respectively. Furthermore, amplification of HSF1 was correlated with higher HSP90AA1 and HSP90AB1 mRNA expression among the breast cancer cells without amplifications of these two genes. A collection of HSP90AA1, HSP90AB1 and HSF1 amplifications defined a subpopulation of breast cancer with up-regulated HSP90 gene expression, and up-regulated HSP90 expression independently elevated the risk of recurrence of TNBC and poor prognosis of HER2-/ER+ breast cancer. Up-regulated HSP90 mRNA expression represents a confluence of genomic vulnerability that renders HER2 negative breast cancers more aggressive, resulting in poor prognosis. Targeting breast cancer with up-regulated HSP90 may potentially improve the effectiveness of clinical intervention in this disease.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
82.9
作者：
通讯作者：
--
DOI：
10.1073/pnas.0903392106
发表时间：
2009-05-19
影响因子：
11.1
作者：
Caldas-Lopes, Eloisi;Cerchietti, Leandro;Chiosis, Gabriela
通讯作者：
Chiosis, Gabriela
影响因子：
3.8
作者：
Karn, Thomas;Metzler, Dirk;Rody, Achim
通讯作者：
Rody, Achim
影响因子：
82.9
作者：
Li, Yang;Zou, Lihua;Li, Qiyuan;Haibe-Kains, Benjamin;Tian, Ruiyang;Li, Yan;Desmedt, Christine;Sotiriou, Christos;Szallasi, Zoltan;Iglehart, J. Dirk;Richardson, Andrea L.;Wang, Zhigang Charles
通讯作者：
Wang, Zhigang Charles