RUNX2 and TAZ-dependent signaling pathways regulate soluble E-Cadherin levels and tumorsphere formation in breast cancer cells
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Jessica L. Brusgard1,3, Moran Choe3,9, Saranya Chumsri2,8, Keli Renoud3, Alexander D. MacKerell Jr.4, Marius Sudol5, Antonino Passaniti6,7
1Program in Molecular Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
2Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
3Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
4Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, USA
5Mechanobiology Institute, Department of Physiology, National University of Singapore, Singapore
6Department of Pathology and Department of Biochemistry & Molecular Biology, The Marlene & Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
7The Veteran’s Health Administration Research & Development Service, Baltimore, MD, USA
8Department of Hematology/Oncology, Mayo Clinic, Jacksonville, FL, USA
9Laboratory of Genitourinary Cancer Pathogenesis, NCI, Bethesda, MD, USA
Antonino Passaniti, e-mail: email@example.com
Keywords: breast cancer, transcription factors, tumorspheres, therapeutics
Received: February 16, 2015 Accepted: July 08, 2015 Published: July 20, 2015
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.
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