Lunatic fringe deficiency cooperates with the Met/Caveolin gene amplicon to induce basal-like breast cancer

Keli Xu; Jerry Usary; Philaretos C Kousis; Aleix Prat; Dong-Yu Wang; Jessica R Adams; Wei Wang; Amanda J Loch; Tao Deng; Wei Zhao; Robert Darrell Cardiff; Keejung Yoon; Nicholas Gaiano; Vicki Ling; Joseph Beyene; Eldad Zacksenhaus; Tom Gridley; Wey L Leong; Cynthia J Guidos; Charles M Perou; Sean E Egan

doi:10.1016/j.ccr.2012.03.041

Lunatic fringe deficiency cooperates with the Met/Caveolin gene amplicon to induce basal-like breast cancer

Cancer Cell. 2012 May 15;21(5):626-641. doi: 10.1016/j.ccr.2012.03.041.

Authors

Keli Xu¹, Jerry Usary², Philaretos C Kousis¹, Aleix Prat², Dong-Yu Wang³, Jessica R Adams⁴, Wei Wang¹, Amanda J Loch¹, Tao Deng⁵, Wei Zhao², Robert Darrell Cardiff⁶, Keejung Yoon⁷, Nicholas Gaiano⁷, Vicki Ling⁸, Joseph Beyene⁹, Eldad Zacksenhaus⁵, Tom Gridley¹⁰, Wey L Leong³, Cynthia J Guidos¹¹, Charles M Perou², Sean E Egan¹²

Affiliations

¹ Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, M5G 1L7, Canada.
² Lineberger Comprehensive Cancer Center, Departments of Genetics and Pathology, University of North Carolina, Chapel Hill, NC 27599, USA.
³ 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.
⁴ 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.
⁵ Division of Cell and Molecular Biology, Toronto General Research Institute, University Health Network, Toronto, ON M5S 1A1, Canada.
⁶ Center for Comparative Medicine, University of California, Davis, CA 95616, USA.
⁷ Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁸ 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.
⁹ Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, ON, M5G 1L7, Canada.
¹⁰ Center for Molecular Medicine, Maine Medical Center Research Institute, 81 Research Drive, Scarborough, ME 04074, USA.
¹¹ 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.
¹² 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: [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Breast Neoplasms / enzymology*
Breast Neoplasms / genetics
Breast Neoplasms / pathology
Calcium-Binding Proteins / metabolism
Caveolins / genetics
Caveolins / metabolism*
Cell Proliferation
Cell Transformation, Neoplastic / genetics
Cell Transformation, Neoplastic / metabolism*
Cell Transformation, Neoplastic / pathology
Cells, Cultured
Claudins / metabolism
Databases, Genetic
Female
Gene Expression Profiling / methods
Gene Expression Regulation, Developmental
Gene Expression Regulation, Neoplastic
Glycosyltransferases / deficiency
Glycosyltransferases / genetics
Glycosyltransferases / metabolism*
Humans
Immunohistochemistry
Intercellular Signaling Peptides and Proteins / metabolism
Jagged-1 Protein
Mammary Glands, Animal / enzymology*
Mammary Glands, Animal / growth & development
Mammary Glands, Animal / pathology
Mammary Glands, Animal / transplantation
Mammary Neoplasms, Experimental / enzymology*
Mammary Neoplasms, Experimental / genetics
Mammary Neoplasms, Experimental / pathology
Membrane Proteins / metabolism
Mice
Mice, Knockout
Middle Aged
Neoplastic Stem Cells / enzymology*
Neoplastic Stem Cells / pathology
Neoplastic Stem Cells / transplantation
Oligonucleotide Array Sequence Analysis
Proto-Oncogene Proteins c-met / genetics
Proto-Oncogene Proteins c-met / metabolism*
Receptor, IGF Type 1 / metabolism
Receptors, Notch / metabolism
Serrate-Jagged Proteins
Signal Transduction

Substances

Calcium-Binding Proteins
Caveolins
Claudins
Intercellular Signaling Peptides and Proteins
JAG1 protein, human
Jag1 protein, mouse
Jagged-1 Protein
Membrane Proteins
Receptors, Notch
Serrate-Jagged Proteins
Glycosyltransferases
LFNG protein, human
Lfng protein, mouse
MET protein, human
Proto-Oncogene Proteins c-met
Receptor, IGF Type 1

Associated data

GEO/GSE28712
GEO/GSE35855

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding