Tetraspanin CD151 is increasingly implicated as a multifaceted mediator of cancer development and progression. Here we investigated the role of CD151 in breast cancer in the context of the Wnt oncogenic activation. Our data showed that removal of one or both of CD151 alleles in the MMTV-Wnt1 model significantly decreased the tumor-free survival of mice from 34 weeks on average to 22 weeks and 18 weeks, respectively. This effect coincided with an accelerated tumor growth and an increased number of Ki-67+ proliferative cells. Mechanistically, the CD151-deficient tumors were largely ER+, and exhibited hyperactivation of the Wnt pathway as reflected by a marked upregulation in β-catenin and Cyclin D1, and their target genes. In addition, E-cadherin displayed a cytosolic distribution and transcription factor Snail was markedly upregulated. Collectively, this data implies that CD151 suppresses the Wnt1-driven tumorigenesis, at least in part, via counteracting the epithelial-mesenchymal transition (EMT)-like program in luminal epithelial cells. Meanwhile, the proportion of tumor cells expressing CK5 or p63, the biomarkers of myoepithelial/basal cells, markedly decreased in the absence of CD151. This change was accompanied by a decreased invasiveness of tumors and their incompetence to form a long-term cell culture. Consistent with this basal cell-linked role, the CD151 downregulation impairs mammosphere formation in MCF-10A cells and the defect was rescued by re-expression of intact CD151 ORF, but not its integrin binding-defective mutant. Overall, our study suggests that CD151 is a key player in the Wnt oncogene-driven tumorigenesis and impacts breast cancer malignancy in a cell type-dependent manner.

中文翻译：

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四跨膜蛋白CD151的删除改变Wnt癌基因诱导的乳腺肿瘤发生：一种细胞类型相关的功能和信号。

四跨膜蛋白CD151越来越多地牵涉到癌症发展和进展的多方面介质。在这里，我们研究了W151致癌激活背景下CD151在乳腺癌中的作用。我们的数据表明，MMTV-Wnt1模型中一个或两个CD151等位基因的去除显着降低了小鼠的无瘤生存期，从平均34周分别降至22周和18周。该作用与肿瘤生长加快和Ki-67 +增殖细胞数量增加相吻合。从机理上讲，缺乏CD151的肿瘤主要是ER +，并且表现出Wnt通路的过度激活，这由β-catenin和Cyclin D1及其靶基因的明显上调所反映。另外，E-钙粘着蛋白表现出胞质分布，并且转录因子Snail明显上调。总的来说，该数据暗示CD151至少部分地通过抵消腔上皮细胞中的上皮-间质转化（EMT）样程序来抑制Wnt1驱动的肿瘤发生。同时，在没有CD151的情况下，表达CK5或p63（肌上皮/基底细胞的生物标志物）的肿瘤细胞的比例显着降低。这种变化伴随着肿瘤侵袭性的降低以及它们不能形成长期细胞培养物。与此基础细胞链接的作用相一致，CD151的下调会损害MCF-10A细胞中的乳球形成，并且通过完整表达CD151 ORF（但不是其整合素结合缺陷型突变体）的重新表达来挽救该缺陷。总体，