Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):2778-83. doi: 10.1073/pnas.1018862108. Epub 2011 Jun 1.
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 (TICs) 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 50 p53 null mammary tumors compared with 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 compared with the more common adenocarcinomas arising in the same model, thus providing a unique preclinical mouse model to investigate the therapeutic response of TICs.
Claudin-low 亚型是最近鉴定出的一种罕见的人乳腺癌分子亚型，其特点是紧密连接和黏附连接基因表达水平低，上皮间质转化 (EMT) 基因表达水平高。这些肿瘤富含源自人肿瘤起始细胞 (TICs) 和人乳腺干细胞的基因表达特征。通过跨物种分析，我们发现了具有与人 Claudin-low 肿瘤相似基因表达特征的小鼠乳腺肿瘤，并且也富含人 TIC 特征。这种 Claudin-low 肿瘤同样罕见，但来自多种不同的小鼠模型，包括 p53 缺失的移植模型。在此，我们对 50 个 p53 缺失的乳腺肿瘤进行了分子特征分析，与其他小鼠模型和人类乳腺癌肿瘤亚型进行了比较。与人类肿瘤相似，p53 缺失的小鼠肿瘤分为多个分子亚型，包括两个基底样、一个腔样、一个 Claudin-low 样，以及一个仅存在于该模型中的亚型。Claudin-low 肿瘤也表现出 EMT 诱导物的高基因表达、miR-200 家族的低表达，以及 Claudin3 和 E-钙黏蛋白的低表达或缺失。这些小鼠亚型还具有独特的基因组 DNA 拷贝数变化，其中一些在其同源的人类亚型中也有类似的改变。最后，有限稀释移植显示，与同一模型中更为常见的腺癌相比，p53 缺失 Claudin-low 肿瘤中 TICs 高度富集，从而为研究 TICs 的治疗反应提供了一个独特的临床前小鼠模型。
