Brusgard Jessica L, Choe Moran, Chumsri Saranya, Renoud Keli, MacKerell Alexander D, Sudol Marius, Passaniti Antonino
Program in Molecular Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.
Oncotarget. 2015 Sep 29;6(29):28132-50. doi: 10.18632/oncotarget.4654.
Intratumoral heterogeneity and treatment resistance drive breast cancer (BC) metastasis and recurrence. The RUNX2 transcription factor is upregulated in early stage luminal BC. However, the precise mechanism by which RUNX2 regulates an oncogenic phenotype in luminal BCs remains an enigma. We show that RUNX2 is predictive of poor overall survival in BC patients. RUNX2 associated with the TAZ transcriptional co-activator to promote a tumorigenic phenotype that was inhibited by knockdown of TAZ. RUNX2 increased endogenous TAZ translocation to the nucleus, which was prevented by inhibiting RUNX2. RUNX2/TAZ interaction was associated with ectodomain shedding of an oncogenic soluble E-Cadherin fragment (sE-Cad), which is known to cooperate with human epidermal growth factor receptor-2 (HER2/ErbB2) to increase BC growth. Neutralizing E-Cadherin antibodies or TAZ knockdown reduced the levels of sE-Cad in RUNX2-expressing BC cells and inhibited tumorsphere formation. RUNX2 expression also increased HER2-mediated tumorsphere size, which was reduced after treatment with the HER2-targeting agents Herceptin and lapatinib. These data support a novel role for RUNX2 in promoting an oncogenic phenotype in luminal BC in the context of TAZ, sE-Cad, and HER2. Using this signaling pathway to monitor BC cell oncogenic activity will accelerate the discovery of new therapeutic modalities to treat BC patients.
肿瘤内异质性和治疗抗性驱动乳腺癌（BC）转移和复发。RUNX2转录因子在早期管腔型BC中上调。然而，RUNX2调节管腔型BC致癌表型的确切机制仍是一个谜。我们表明，RUNX2可预测BC患者的总体生存率较差。RUNX2与TAZ转录共激活因子相关联，以促进致癌表型，而TAZ的敲低可抑制该表型。RUNX2增加内源性TAZ向细胞核的转位，抑制RUNX2可阻止这种转位。RUNX2/TAZ相互作用与致癌性可溶性E-钙黏蛋白片段（sE-Cad）的胞外域脱落有关，已知该片段与人表皮生长因子受体2（HER2/ErbB2）协同作用以促进BC生长。中和E-钙黏蛋白抗体或敲低TAZ可降低表达RUNX2的BC细胞中sE-Cad的水平，并抑制肿瘤球形成。RUNX2表达还增加了HER2介导的肿瘤球大小，用HER2靶向药物赫赛汀和拉帕替尼治疗后肿瘤球大小减小。这些数据支持RUNX2在TAZ、sE-Cad和HER2背景下促进管腔型BC致癌表型方面的新作用。利用该信号通路监测BC细胞的致癌活性将加速发现治疗BC患者的新治疗方式。
