RUNX2 and TAZ-dependent signaling pathways regulate soluble E-Cadherin levels and tumorsphere formation in breast cancer cells.
RUNX2 and TAZ-dependent signaling pathways regulate soluble E-Cadherin levels and tumorsphere formation in breast cancer cells.
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DOI：
10.18632/oncotarget.4654
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发表时间：
2015-09-29
期刊：
影响因子：
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通讯作者：
Passaniti A
中科院分区：
文献类型：
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作者：
Brusgard JL;Choe M;Chumsri S;Renoud K;MacKerell AD Jr;Sudol M;Passaniti A
肿瘤内异质性和治疗抗性驱动乳腺癌（BC）转移和复发。RUNX 2转录因子在早期管腔型BC中上调。然而，RUNX 2调节管腔BC中致癌表型的确切机制仍然是一个谜。我们发现RUNX 2可以预测BC患者的总体生存率。RUNX 2与TAZ转录辅激活因子相关，以促进通过敲低TAZ抑制的致瘤表型。RUNX 2增加了内源性TAZ向细胞核的转运，这可以通过抑制RUNX 2来阻止。RUNX 2/TAZ相互作用与致癌性可溶性E-钙粘蛋白片段（sE-Cad）的胞外域脱落相关，已知sE-Cad与人表皮生长因子受体-2（HER 2/ErbB 2）合作增加BC生长。中和E-钙粘蛋白抗体或TAZ敲低降低了表达RUNX 2的BC细胞中sE-Cad的水平，并抑制肿瘤球形成。RUNX 2表达还增加了HER 2介导的肿瘤球大小，在使用HER 2靶向药物赫赛汀和拉帕替尼治疗后，肿瘤球大小减少。这些数据支持RUNX 2在TAZ、sE-Cad和HER 2背景下促进管腔BC中致癌表型的新作用。使用这种信号通路来监测BC细胞致癌活性将加速发现治疗BC患者的新治疗方式。
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.