MUC1 triggers lineage plasticity of Her2 positive mammary tumors
MUC1 triggers lineage plasticity of Her2 positive mammary tumors
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MUC1触发Her2阳性乳腺肿瘤的谱系可塑性
DOI：
10.1038/s41388-022-02320-y
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发表时间：
2022-04-23
期刊：
影响因子：
8
通讯作者：
Huang，Lei
中科院分区：
文献类型：
--
作者：
Pang，Zhi;Dong，Xinran;Huang，Lei
粘蛋白1 （MUC1）和人表皮生长因子受体2 （HER2）的异常过表达在乳腺癌中经常被观察到。然而，伴随MUC1/HER2在乳腺癌发展中的作用尚未得到充分阐明。通过对公开微阵列数据集的分析，揭示了双重MUC1和HER2阳性与更差的临床结果之间的相关性，我们建立了一个HER2和MUC1细胞质结构域（MUC1- cd）过表达的小鼠模型，以研究它们在乳腺癌发生中的相互作用。Her2和MUC1-CD的共表达赋予了生长优势，促进了自发性乳腺肿瘤的发展。基因组分析表明，MUC1-CD和Her2的强制表达诱导了乳腺肿瘤谱系的可塑性，这种可塑性与基因重编程和乳腺干细胞富集有关。通过功能获得和功能丧失策略，我们发现Her2和MUC1-CD的共表达与肿瘤中三羧酸（TCA）循环基因的下调有关。重要的是，MUC1-CD诱导的TCA循环基因的减少与HER2+乳腺癌患者的不良预后显著相关。此外，MUC1通过诱导Her2/Egfr二聚化来增强Her2信号通路。这些发现共同证明了MUC1- cd /Her2在塑造乳腺肿瘤景观中的重要作用，并强调了MUC1在Her2 +乳腺癌患者中的预后和治疗意义。
Aberrant overexpression of mucin 1 (MUC1) and human epidermal growth factor receptor 2 (HER2) are often observed in breast cancer. However, the role of concomitant MUC1/HER2 in the development of breast cancer has not been fully illustrated. Following analysis of public microarray datasets that revealed a correlation between double MUC1 and HER2 positivity and a worse clinical outcome, we generated a mouse model overexpressing both Her2 and MUC1 cytoplasmic domain (MUC1-CD) to investigate their interaction in mammary carcinogenesis. Coexpression of Her2 and MUC1-CD conferred a growth advantage and promoted the development of spontaneous mammary tumors. Genomic analysis revealed that enforced expression of MUC1-CD and Her2 induces mammary tumor lineage plasticity, which is supported by gene reprogramming and mammary stem cell enrichment. Through gain- and loss-of-function strategies, we show that coexpression of Her2 and MUC1-CD is associated with downregulation of tricarboxylic acid (TCA) cycle genes in tumors. Importantly, the reduction in TCA cycle genes induced by MUC1-CD was found to be significantly connected to poor prognosis in HER2+breast cancer patients. In addition, MUC1 augments the Her2 signaling pathway by inducing Her2/Egfr dimerization. These findings collectively demonstrate the vital role of MUC1-CD/Her2 collaboration in shaping the mammary tumor landscape and highlight the prognostic and therapeutic implications of MUC1 in patients with HER2+breast cancer.