title: The ubiquitin E3 ligase ITCH enhances breast tumor progression by inhibiting the Hippo tumor suppressor pathway.
abstract: The Hippo kinase pathway is emerging as a conserved signaling pathway that is essential for organ growth and tumorigenesis. Recently, we reported that the ubiquitin E3 ligase ITCH negatively regulates LATS1, thereby increasing YAP activity, which leads to increased cell proliferation and decreased apoptosis. Here, we investigated the role of ITCH in breast tumorigenesis. In particular, we show that ITCH enhances epithelial-to-mesenchymal transition (EMT) through boosting YAP oncogenic function. By contrast, a point mutation in the catalytic domain or WW1 domain of ITCH abolished its EMT-mediated effects. Furthermore, while overexpression of ITCH expression in breast cells is associated with increased incidence of mammary tumor formation and progression, its knockdown inhibited breast cancer cell tumorigenicity and metastasis. Importantly, YAP knockdown was able to attenuate ITCH pro-tumorigenic functions. Lastly, we found that ITCH expression is significantly upregulated in invasive and metastatic breast cancer cases and is associated with worse survival. Together, our results reveal that ITCH pro-tumorigenic functions in breast cancer are mediated, at least in part, through inactivation of the Hippo tumor suppressor pathway.
authors.affiliation: The Lautenberg Center for Immunology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel. Al Quds-Bard College, Al-Quds University, Abu Dies, East Jerusalem, Palestine.
authors.forename: Zaidoun
authors.initials: Z
authors.lastname: Salah
authors.affiliation: The Lautenberg Center for Immunology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Ella
authors.initials: E
authors.lastname: Itzhaki
authors.affiliation: The Lautenberg Center for Immunology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel. Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
authors.forename: Rami I
authors.initials: RI
authors.lastname: Aqeilan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D000090683:Hippo Signaling Pathway; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000378:metabolism / Q000401:mortality / Q000556:secondary*; D015674:Mammary Neoplasms, Animal / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014157:Transcription Factors; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D014452:Ubiquitins / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D014157:Transcription Factors; D014452:Ubiquitins; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C432966:ITCH protein, human; D044767:Ubiquitin-Protein Ligases; C092745:LATS1 protein, human; D017346:Protein Serine-Threonine Kinases