title: Molecular profiling and computational network analysis of TAZ-mediated mammary tumorigenesis identifies actionable therapeutic targets.
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.
authors.affiliation: Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA.
authors.forename: Costa
authors.initials: C
authors.lastname: Frangou
authors.affiliation: Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA.
authors.forename: Ying-Wei
authors.initials: YW
authors.lastname: Li
authors.affiliation: Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA.
authors.forename: He
authors.initials: H
authors.lastname: Shen
authors.affiliation: Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA.
authors.forename: Nuo
authors.initials: N
authors.lastname: Yang
authors.affiliation: Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA.
authors.forename: Kayla E
authors.initials: KE
authors.lastname: Wilson
authors.affiliation: Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA.
authors.forename: Maxime
authors.initials: M
authors.lastname: Blijlevens
authors.affiliation: Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Biochemistry, School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, 14260, USA.
authors.forename: Norma J
authors.initials: NJ
authors.lastname: Nowak
authors.affiliation: Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D000069439:Dasatinib; D005434:Flow Cytometry; D064593:Heterografts; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D051379:Mice; D016513:Mice, SCID; D014411:Neoplastic Stem Cells; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000235:genetics*; D013844:Thiazoles / Q000494:pharmacology; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D059467:Transcriptome / Q000235:genetics*; D014161:Transduction, Genetic; D014162:Transfection; D064726:Triple Negative Breast Neoplasms / Q000235:genetics*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; C551991:WWTR1 protein, human; D000069439:Dasatinib