Comparative oncogenomics identifies breast tumors enriched in functional tumor initiating cells. Mus musculus

The claudin-low subtype is a recently identified rare molecular subtype of human breast cancer that expresses low levels of tight and adherens junction genes and shows high expression of epithelial-to-mesenchymal transition (EMT) genes. These tumors are enriched in gene expression signatures derived from human tumor initiating cells (TIC) and human mammary stem cells. Through cross-species analysis, we discovered mouse mammary tumors that have similar gene expression characteristics as human claudin-low tumors and were also enriched for the human TIC signature. Such claudin-low tumors were similarly rare, but came from a number of distinct mouse models including the p53 null transplant model. Here we present a molecular characterization of fifty p53 null mammary tumors as compared to other mouse models and human breast tumor subtypes. Similar to human tumors, the murine p53 null tumors fell into multiple molecular subtypes including two basal-like, a luminal, a claudin-low, and a subtype unique to this model. The claudin-low tumors also showed high gene expression of EMT inducers, low expression of the miR-200 family, and low to absent expression of both claudin 3 and E-cadherin. These murine subtypes also contained distinct genomic DNA copy number changes some of which are similarly altered in their cognate human subtype counterpart. Finally, limiting dilution transplantation revealed that p53 null claudin-low tumors are highly enriched for TICs as compared to the more common adenocarcinomas arising in the same model, thus providing a novel preclinical mouse model to investigate the therapeutic response of TICs. Overall design: 107 Agilent CGH and expression microarrays

克劳丁低表达亚型（claudin-low subtype）是近年发现的一种罕见人类乳腺癌分子亚型，其紧密连接与黏附连接基因表达水平低下，而上皮间质转化（epithelial-to-mesenchymal transition, EMT）相关基因呈高表达。这类肿瘤富含源自人类肿瘤起始细胞（tumor initiating cells, TIC）与人类乳腺干细胞的基因表达特征。通过跨物种分析，我们发现了基因表达特征与人类克劳丁低表达肿瘤高度相似的小鼠乳腺肿瘤，这类小鼠肿瘤同样富集人类TIC特征。此类克劳丁低表达肿瘤同样极为罕见，且源自多种不同的小鼠模型，其中包括p53缺失型（p53 null）移植模型。本研究对50株p53缺失型小鼠乳腺肿瘤进行了分子特征解析，并与其他小鼠模型及人类乳腺癌亚型展开对比分析。与人类肿瘤情况一致，小鼠p53缺失型肿瘤可划分为多种分子亚型，包括2株基底样型、1株腔面型、1株克劳丁低表达型，以及本模型特有的一种亚型。该克劳丁低表达亚型肿瘤同样呈现EMT诱导因子高表达、miR-200家族低表达，以及紧密连接蛋白3（claudin 3）与E-钙粘蛋白（E-cadherin）低表达甚至缺失的特征。这些小鼠肿瘤亚型还存在独特的基因组DNA拷贝数变异，其中部分变异在其对应的人类同源亚型中同样存在改变。最后，极限稀释移植实验（limiting dilution transplantation）结果显示，相较于同一模型中更为常见的腺癌，p53缺失型克劳丁低表达肿瘤的TIC富集度显著更高，这为研究TIC的治疗应答提供了全新的临床前小鼠模型。整体实验设计：107份安捷伦比较基因组杂交（comparative genomic hybridization, CGH）与表达谱微阵列检测数据。