title: Lunatic fringe deficiency cooperates with the Met/Caveolin gene amplicon to induce basal-like breast cancer.
abstract: Basal-like breast cancers (BLBC) express a luminal progenitor gene signature. Notch receptor signaling promotes luminal cell fate specification in the mammary gland, while suppressing stem cell self-renewal. Here we show that deletion of Lfng, a sugar transferase that prevents Notch activation by Jagged ligands, enhances stem/progenitor cell proliferation. Mammary-specific deletion of Lfng induces basal-like and claudin-low tumors with accumulation of Notch intracellular domain fragments, increased expression of proliferation-associated Notch targets, amplification of the Met/Caveolin locus, and elevated Met and Igf-1R signaling. Human BL breast tumors, commonly associated with JAGGED expression, elevated MET signaling, and CAVEOLIN accumulation, express low levels of LFNG. Thus, reduced LFNG expression facilitates JAG/NOTCH luminal progenitor signaling and cooperates with MET/CAVEOLIN basal-type signaling to promote BLBC.
authors.affiliation: Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, M5G 1L7, Canada.
authors.forename: Keli
authors.initials: K
authors.lastname: Xu
authors.affiliation: Lineberger Comprehensive Cancer Center, Departments of Genetics and Pathology, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Jerry
authors.initials: J
authors.lastname: Usary
authors.affiliation: Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, M5G 1L7, Canada.
authors.forename: Philaretos C
authors.initials: PC
authors.lastname: Kousis
authors.affiliation: Lineberger Comprehensive Cancer Center, Departments of Genetics and Pathology, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Aleix
authors.initials: A
authors.lastname: Prat
authors.affiliation: The Campbell Family Cancer Research Institute and Surgical Oncology Princess Margaret Hospital, and the Department of General Surgery, University Health Network, Toronto, ON M5S 1A1, Canada.
authors.forename: Dong-Yu
authors.initials: DY
authors.lastname: Wang
authors.affiliation: Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A1, Canada.
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Adams
authors.affiliation: Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, M5G 1L7, Canada.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, M5G 1L7, Canada.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Loch
authors.affiliation: Division of Cell and Molecular Biology, Toronto General Research Institute, University Health Network, Toronto, ON M5S 1A1, Canada.
authors.forename: Tao
authors.initials: T
authors.lastname: Deng
authors.affiliation: Lineberger Comprehensive Cancer Center, Departments of Genetics and Pathology, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Center for Comparative Medicine, University of California, Davis, CA 95616, USA.
authors.forename: Robert Darrell
authors.initials: RD
authors.lastname: Cardiff
authors.affiliation: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Keejung
authors.initials: K
authors.lastname: Yoon
authors.affiliation: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Gaiano
authors.affiliation: Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, M5G 1L7, Canada; Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, ON, M5G 1L7, Canada.
authors.forename: Vicki
authors.initials: V
authors.lastname: Ling
authors.affiliation: Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, ON, M5G 1L7, Canada.
authors.forename: Joseph
authors.initials: J
authors.lastname: Beyene
authors.affiliation: Division of Cell and Molecular Biology, Toronto General Research Institute, University Health Network, Toronto, ON M5S 1A1, Canada.
authors.forename: Eldad
authors.initials: E
authors.lastname: Zacksenhaus
authors.affiliation: Center for Molecular Medicine, Maine Medical Center Research Institute, 81 Research Drive, Scarborough, ME 04074, USA.
authors.forename: Tom
authors.initials: T
authors.lastname: Gridley
authors.affiliation: The Campbell Family Cancer Research Institute and Surgical Oncology Princess Margaret Hospital, and the Department of General Surgery, University Health Network, Toronto, ON M5S 1A1, Canada.
authors.forename: Wey L
authors.initials: WL
authors.lastname: Leong
authors.affiliation: Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, M5G 1L7, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1A1, Canada.
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Guidos
authors.affiliation: Lineberger Comprehensive Cancer Center, Departments of Genetics and Pathology, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
authors.affiliation: Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, M5G 1L7, Canada; The Campbell Family Cancer Research Institute and Surgical Oncology Princess Margaret Hospital, and the Department of General Surgery, University Health Network, Toronto, ON M5S 1A1, Canada. Electronic address: segan@sickkids.ca.
authors.forename: Sean E
authors.initials: SE
authors.lastname: Egan
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D022461:Caveolins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D057167:Claudins / Q000378:metabolism; D030541:Databases, Genetic; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D016695:Glycosyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D000072100:Jagged-1 Protein; D008321:Mammary Glands, Animal / Q000201:enzymology* / Q000254:growth & development / Q000473:pathology / Q000637:transplantation; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000201:enzymology* / Q000473:pathology / Q000637:transplantation; D020411:Oligonucleotide Array Sequence Analysis; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction
chemical_list: D002135:Calcium-Binding Proteins; D022461:Caveolins; D057167:Claudins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D016695:Glycosyltransferases; C498393:LFNG protein, human; C498392:Lfng protein, mouse; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D017526:Receptor, IGF Type 1