Bui Tung, Schade Babette, Cardiff Robert D, Aina Olulanu H, Sanguin-Gendreau Virginie, Muller William J
Goodman Cancer Center, McGill University, Montreal, QC H3A 1A3, Canada.
Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada.
Proc Natl Acad Sci U S A. 2017 Jan 31;114(5):E707-E716. doi: 10.1073/pnas.1610383114. Epub 2017 Jan 17.
Aberrant activation of β-catenin through its activity as a transcription factor has been observed in a large proportion of human malignancies. Despite the improved understanding of the β-catenin signaling pathway over the past three decades, attempts to develop therapies targeting β-catenin remain challenging, and none of these targeted therapies have advanced to the clinic. In this study, we show that part of the challenge in antagonizing β-catenin is caused by its dual functionality as a cell adhesion molecule and a signaling molecule. In a mouse model of basal ErbB2 receptor tyrosine kinase 2 (ErbB2)-positive breast cancer (ErbB2), which exhibits aberrant β-catenin nuclear signaling, β-catenin haploinsufficiency induced aggressive tumor formation and metastasis by promoting the disruption of adherens junctions, dedifferentiation, and an epithelial to mesenchymal transition (EMT) transcriptional program. In contrast to the accelerated tumor onset observed in the haploid-insufficient ErbB2 tumors, deletion of both β-catenin alleles in the ErbB2 model had only a minor impact on tumor onset that further correlated with the retention of normal adherens junctions. We further showed that retention of adherens junctional integrity was caused by the up-regulation of the closely related family member plakoglobin (γ-catenin) that maintained both adherens junctions and the activation of Wnt target genes. In contrast to the ErbB2 basal tumor model, modulation of β-catenin levels had no appreciable impact on tumor onset in an ErbB2-driven model of luminal breast cancer [murine mammary tumor virus promoter (MMTV-NIC)]. These observations argue that the balance of junctional and nuclear β-catenin activity has a profound impact on tumor progression in this basal model of ErbB2-positive breast cancer.
在大部分人类恶性肿瘤中都观察到了β-连环蛋白作为转录因子的异常激活。尽管在过去三十年中人们对β-连环蛋白信号通路的理解有所提高，但开发针对β-连环蛋白的疗法仍然具有挑战性，且这些靶向疗法均未进入临床阶段。在本研究中，我们表明拮抗β-连环蛋白面临的部分挑战是由其作为细胞粘附分子和信号分子的双重功能所致。在基底型表皮生长因子受体2（ErbB2）阳性乳腺癌（ErbB2）的小鼠模型中，该模型表现出异常的β-连环蛋白核信号，β-连环蛋白单倍体不足通过促进紧密连接的破坏、去分化和上皮-间质转化（EMT）转录程序，诱导侵袭性肿瘤形成和转移。与在单倍体不足的ErbB2肿瘤中观察到的肿瘤发病加速相反，在ErbB2模型中删除β-连环蛋白的两个等位基因对肿瘤发病的影响较小，这进一步与正常紧密连接的保留相关。我们进一步表明，紧密连接完整性的保留是由密切相关的家族成员桥粒芯蛋白（γ-连环蛋白）的上调引起的，它维持了紧密连接和Wnt靶基因的激活。与ErbB2基底肿瘤模型相反，在ErbB2驱动的管腔型乳腺癌模型[鼠乳腺肿瘤病毒启动子（MMTV-NIC）]中，调节β-连环蛋白水平对肿瘤发病没有明显影响。这些观察结果表明，在这种基底型ErbB2阳性乳腺癌模型中，连接型和核型β-连环蛋白活性的平衡对肿瘤进展具有深远影响。
