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.
Subject(s)
Breast Neoplasms/enzymology , Caveolins/metabolism , Cell Transformation, Neoplastic/metabolism , Glycosyltransferases/metabolism , Mammary Glands, Animal/enzymology , Mammary Neoplasms, Experimental/enzymology , Neoplastic Stem Cells/enzymology , Proto-Oncogene Proteins c-met/metabolism , Animals , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Calcium-Binding Proteins/metabolism , Caveolins/genetics , Cell Proliferation , Cell Transformation, Neoplastic/genetics , 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 , Humans , Immunohistochemistry , Intercellular Signaling Peptides and Proteins/metabolism , Jagged-1 Protein , Mammary Glands, Animal/growth & development , Mammary Glands, Animal/pathology , Mammary Glands, Animal/transplantation , Mammary Neoplasms, Experimental/genetics , Mammary Neoplasms, Experimental/pathology , Membrane Proteins/metabolism , Mice , Mice, Knockout , Middle Aged , Neoplastic Stem Cells/pathology , Neoplastic Stem Cells/transplantation , Oligonucleotide Array Sequence Analysis , Proto-Oncogene Proteins c-met/genetics , Receptor, IGF Type 1/metabolism , Receptors, Notch/metabolism , Serrate-Jagged Proteins , Signal TransductionABSTRACT
Epithelial-mesenchymal-transition (EMT) tumorigenesis in the mouse was first described over 100 years ago using various terms such as carcinosarcoma and without any comprehension of the underlying mechanisms. Such tumors have been considered artifacts of transplantation and of tissue culture. Recently, EMT tumors have been recognized in mammary glands of genetically engineered mice. This review provides a historical perspective leading to the current status in the context of some of the key molecular biology. The biology of mouse mammary EMT tumorigenesis is discussed with comparisons to human breast cancer.
