Research Papers:
Molecular profiling and computational network analysis of TAZ-mediated mammary tumorigenesis identifies actionable therapeutic targets
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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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PII: 2570