title: Characterization of TAZ domains important for the induction of breast cancer stem cell properties and tumorigenesis.
abstract: The Hippo pathway is an evolutionarily conserved regulator of tissue growth and cell fate during development and regeneration. Conversely, deregulation of the Hippo pathway has been reported in several malignancies. Here, we used integrative functional genomics approaches to identify TAZ, a transcription co-activator and key downstream effector of the Hippo pathway, as an essential driver for the propagation of TNBC malignant phenotype. We further showed in non-transformed human mammary basal epithelial cells that expression of constitutively active TAZ confers cancer stem cell (CSC) traits that are dependent on the TAZ and TEAD interacting domains. In addition, to gain a better understanding of how TAZ functions, we performed genetic-function analysis of TAZ. Significantly, we identified that both the WW and transcriptional activation domains of TAZ are critical for the induced CSC properties as well as tumorigenic potential as manifested in vitro and in human breast cancer xenograft in vivo. Collectively, our data suggest that pharmacological inhibition of TAZ activity may provide a novel means of targeting and eliminating breast CSCs.
authors.affiliation: a Department of Cancer Genetics; Roswell Park Cancer Institute ; Buffalo , NY USA.
authors.forename: Ying-Wei
authors.initials: YW
authors.lastname: Li
authors.forename: He
authors.initials: H
authors.lastname: Shen
authors.forename: Costa
authors.initials: C
authors.lastname: Frangou
authors.forename: Nuo
authors.initials: N
authors.lastname: Yang
authors.forename: Jin
authors.initials: J
authors.lastname: Guo
authors.forename: Bo
authors.initials: B
authors.lastname: Xu
authors.forename: Wiam
authors.initials: W
authors.lastname: Bshara
authors.forename: Lori
authors.initials: L
authors.lastname: Shepherd
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Zhu
authors.forename: Jianmin
authors.initials: J
authors.lastname: Wang
authors.forename: Qiang
authors.initials: Q
authors.lastname: Hu
authors.forename: Song
authors.initials: S
authors.lastname: Liu
authors.forename: Carl D
authors.initials: CD
authors.lastname: Morrison
authors.forename: Peiqing
authors.initials: P
authors.lastname: Sun
authors.forename: Jianmin
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D000090683:Hippo Signaling Pathway; D006801:Humans; D042361:Mammary Glands, Human / Q000166:cytology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000378:metabolism; D000091262:TEA Domain Transcription Factors; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D015533:Transcriptional Activation; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism / Q000473:pathology*
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D000091262:TEA Domain Transcription Factors; C057182:TEAD1 protein, human; D014157:Transcription Factors; D017346:Protein Serine-Threonine Kinases
keywords: Hippo pathway; TAZ; breast cancer; cancer stem cells; mammary tumorigenesis