Transcriptomic classification of genetically engineered mouse models of breast cancer identifies human subtype counterparts.
Transcriptomic classification of genetically engineered mouse models of breast cancer identifies human subtype counterparts.
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DOI：
10.1186/gb-2013-14-11-r125
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发表时间：
2013-11-12
期刊：
影响因子：
12.3
通讯作者：
Perou CM
中科院分区：
文献类型：
--
作者：
Pfefferle AD;Herschkowitz JI;Usary J;Harrell JC;Spike BT;Adams JR;Torres-Arzayus MI;Brown M;Egan SE;Wahl GM;Rosen JM;Perou CM
人类乳腺癌是一种由多种分子亚型组成的异质性疾病。基因工程小鼠模型是在遗传控制和免疫能力条件下体内研究乳腺癌的有用资源。鉴定具有保守人类肿瘤特征的小鼠模型将有助于确定病因，突出突变对通路激活的影响，并应改善临床前药物测试。使用基因表达微阵列测定了 27 个小鼠乳腺癌模型和正常乳腺组织的转录组谱。分层聚类分析确定了 17 种不同的小鼠亚型。使用三个独立的人类乳腺癌数据集进行跨物种分析，确定了八个类似于特定人类乳腺癌亚型的小鼠类别。多种模型与人类基底样肿瘤相关，包括 TgC3(1)-Tag、TgWAP-Myc 和 Trp53-/-。有趣的是，TgWAPCre-Etv6 模型模仿了 HER2 富集亚型，这是一组人类肿瘤，在之前的比较研究中没有对应的小鼠肿瘤。基因特征分析确定了小鼠和人类亚型之间数百个常见表达的途径特征，突出了肿瘤发生的潜在常见遗传驱动因素。这项乳腺癌小鼠模型研究包含迄今为止最大的综合基因组数据集，用于识别人鼠疾病亚型对应物。我们的方法说明了物种之间比较的价值，以识别忠实模仿人类状况的小鼠模型，并表明需要多个基因工程小鼠模型来代表人类乳腺癌的多样性。报告的跨物种关联应指导临床前研究设计期间的模型选择，以确保使用人类疾病亚型的适当代表。
Human breast cancer is a heterogeneous disease consisting of multiple molecular subtypes. Genetically engineered mouse models are a useful resource for studying mammary cancers in vivo under genetically controlled and immune competent conditions. Identifying murine models with conserved human tumor features will facilitate etiology determinations, highlight the effects of mutations on pathway activation, and should improve preclinical drug testing. Transcriptomic profiles of 27 murine models of mammary carcinoma and normal mammary tissue were determined using gene expression microarrays. Hierarchical clustering analysis identified 17 distinct murine subtypes. Cross-species analyses using three independent human breast cancer datasets identified eight murine classes that resemble specific human breast cancer subtypes. Multiple models were associated with human basal-like tumors including TgC3(1)-Tag, TgWAP-Myc and Trp53-/-. Interestingly, the TgWAPCre-Etv6 model mimicked the HER2-enriched subtype, a group of human tumors without a murine counterpart in previous comparative studies. Gene signature analysis identified hundreds of commonly expressed pathway signatures between linked mouse and human subtypes, highlighting potentially common genetic drivers of tumorigenesis. This study of murine models of breast carcinoma encompasses the largest comprehensive genomic dataset to date to identify human-to-mouse disease subtype counterparts. Our approach illustrates the value of comparisons between species to identify murine models that faithfully mimic the human condition and indicates that multiple genetically engineered mouse models are needed to represent the diversity of human breast cancers. The reported trans-species associations should guide model selection during preclinical study design to ensure appropriate representatives of human disease subtypes are used.
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影响因子：
2.7
作者：
Fan C;Prat A;Parker JS;Liu Y;Carey LA;Troester MA;Perou CM
通讯作者：
Perou CM
影响因子：
12.3
作者：
Herschkowitz JI;Simin K;Weigman VJ;Mikaelian I;Usary J;Hu Z;Rasmussen KE;Jones LP;Assefnia S;Chandrasekharan S;Backlund MG;Yin Y;Khramtsov AI;Bastein R;Quackenbush J;Glazer RI;Brown PH;Green JE;Kopelovich L;Furth PA;Palazzo JP;Olopade OI;Bernard PS;Churchill GA;Van Dyke T;Perou CM
通讯作者：
Perou CM
影响因子：
11.2
作者：
Adams, Jessica R.;Xu, Keli;Egan, Sean E.
通讯作者：
Egan, Sean E.
影响因子：
3.8
作者：
Harrell, J. Chuck;Prat, Aleix;Perou, Charles M.
通讯作者：
Perou, Charles M.
DOI：
10.1186/bcr3230
发表时间：
2012-07-19
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Bennett CN;Tomlinson CC;Michalowski AM;Chu IM;Luger D;Mittereder LR;Aprelikova O;Shou J;Piwinica-Worms H;Caplen NJ;Hollingshead MG;Green JE
通讯作者：
Green JE