RUNX2 and TAZ-dependent signaling pathways regulate soluble E-Cadherin levels and tumorsphere formation in breast cancer cells

被引:33
作者
Brusgard, Jessica L. [1 ,3 ]
Choe, Moran [3 ,10 ]
Chumsri, Saranya [2 ,9 ]
Renoud, Keli [3 ]
MacKerell, Alexander D., Jr. [4 ]
Sudol, Marius [5 ]
Passaniti, Antonino [6 ,7 ,8 ]
机构
[1] Univ Maryland, Sch Med, Program Mol Med, Baltimore, MD 21201 USA
[2] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA
[3] Univ Maryland, Sch Med, Greenebaum Canc Ctr, Baltimore, MD 21201 USA
[4] Univ Maryland, Sch Med, Dept Pharmaceut Sci, Baltimore, MD 21201 USA
[5] Natl Univ Singapore, Dept Physiol, Mechanobiol Inst, Singapore 117548, Singapore
[6] Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA
[7] Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Marlene & Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA
[8] Vet Hlth Adm Res & Dev Serv, Baltimore, MD USA
[9] Mayo Clin, Dept Hematol Oncol, Jacksonville, FL 32224 USA
[10] NCI, Lab Genitourinary Canc Pathogenesis, Bethesda, MD 20892 USA
关键词
breast cancer; transcription factors; tumorspheres; therapeutics; EPITHELIAL-MESENCHYMAL TRANSITION; YES-ASSOCIATED PROTEIN; TRANSCRIPTION FACTOR; PREDICTIVE-VALUE; GENE-EXPRESSION; STEM-CELLS; GROWTH; PHOSPHORYLATION; PROLIFERATION; ROLES;
D O I
10.18632/oncotarget.4654
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:28132 / 28150
页数:19
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