title: Loss of CSL Unlocks a Hypoxic Response and Enhanced Tumor Growth Potential in Breast Cancer Cells.
abstract: Notch signaling is an important regulator of stem cell differentiation. All canonical Notch signaling is transmitted through the DNA-binding protein CSL, and hyperactivated Notch signaling is associated with tumor development; thus it may be anticipated that CSL deficiency should reduce tumor growth. In contrast, we report that genetic removal of CSL in breast tumor cells caused accelerated growth of xenografted tumors. Loss of CSL unleashed a hypoxic response during normoxic conditions, manifested by stabilization of the HIF1α protein and acquisition of a polyploid giant-cell, cancer stem cell-like, phenotype. At the transcriptome level, loss of CSL upregulated more than 1,750 genes and less than 3% of those genes were part of the Notch transcriptional signature. Collectively, this suggests that CSL exerts functions beyond serving as the central node in the Notch signaling cascade and reveals a role for CSL in tumorigenesis and regulation of the cellular hypoxic response.
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Eike-Benjamin
authors.initials: EB
authors.lastname: Braune
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Yat Long
authors.initials: YL
authors.lastname: Tsoi
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Yee Peng
authors.initials: YP
authors.lastname: Phoon
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, 17177 Stockholm, Sweden; Turku Centre for Biotechnology, Abo Akademi University and University of Turku, 20520 Turku, Finland.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Landor
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Helena
authors.initials: H
authors.lastname: Silva Cascales
authors.affiliation: Rheumatology Unit, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, 17176 Stockholm, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ramsköld
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Qiaolin
authors.initials: Q
authors.lastname: Deng
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Arne
authors.initials: A
authors.lastname: Lindqvist
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Lian
authors.affiliation: Turku Centre for Biotechnology, Abo Akademi University and University of Turku, 20520 Turku, Finland.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Sahlgren
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, 17177 Stockholm, Sweden. Electronic address: shaobo.jin@ki.se.
authors.forename: Shao-Bo
authors.initials: SB
authors.lastname: Jin
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, 17177 Stockholm, Sweden. Electronic address: urban.lendahl@ki.se.
authors.forename: Urban
authors.initials: U
authors.lastname: Lendahl
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000235:genetics*; D051379:Mice; D008938:Mitosis / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D051880:Receptors, Notch / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D059467:Transcriptome / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C497570:RBPJ protein, human; D051880:Receptors, Notch
keywords: Notch signaling; breast cancer; mitosis; transcriptome; xenograft