Oncotarget

Research Papers:

Molecular profiling and computational network analysis of TAZ-mediated mammary tumorigenesis identifies actionable therapeutic targets

Costa Frangou _, Ying-Wei Li, He Shen, Nuo Yang, Kayla E. Wilson, Maxime Blijlevens, Jin Guo, Norma J. Nowak and Jianmin Zhang

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Oncotarget. 2014; 5:12166-12176. https://doi.org/10.18632/oncotarget.2570

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Abstract

Costa Frangou1,*, Ying-Wei Li1,*, He Shen1, Nuo Yang1, Kayla E. Wilson1, Maxime Blijlevens1, Jin Guo1, Norma J. Nowak2, Jianmin Zhang1

1Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA

2Department of Biochemistry, School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, 14260, USA

*These authors contributed equally to this work

Correspondence to:

Jianmin Zhang, e-mail: [email protected]

Keywords: breast cancer, TAZ, tumor-initiating cells, RNA sequencing, Dasatinib

Received: August 07, 2014     Accepted: October 03, 2014     Published: October 24, 2014

ABSTRACT

Triple-negative breast cancer (TNBC) accounts for approximately 15–20% of all breast cancer (BC) cases and contributes disproportionately to BC mortality. TAZ, a key transducer of the Hippo pathway, has recently been demonstrated to confer breast cancer stem cell (CSC) traits. However, TAZ target genes and the underlying transcriptional regulatory pathways responsible for the CSC phenomenon remain unknown. Here, we demonstrate that the oncogenic activity of TAZ is essential for propagation of the malignant phenotype. We further show that constitutively active TAZ tumor-derived cells exhibit unique tumor-initiating properties, including increased self-renewal and metastatic seeding potential, acquired chemotherapy resistance and the ability to efficiently regenerate tumor formation in vivo. Combined digital RNA expression analysis and computational network approaches identify several signaling pathways that distinguish breast cancer tumor-initiating cells (T-ICs) from bulk tumor cells. We demonstrate the utility of this approach by repositioning the small molecule tyrosine kinase inhibitor, Dasatinib, which selectively targets T-ICs and inhibits TNBC growth in vivo.


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