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

Cancer Cell. 2012 May 15;21(5):626-41. doi: 10.1016/j.ccr.2012.03.041.

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