title: Manic fringe promotes a claudin-low breast cancer phenotype through notch-mediated PIK3CG induction.
abstract: Claudin-low breast cancer (CLBC) is a poor prognosis disease biologically characterized by stemness and mesenchymal features. These tumors disproportionately affect younger patients and women with African ancestry, causing significant morbidity and mortality, and no effective targeted therapy exists at present. CLBC is thought to originate from mammary stem cells, but little is known on how or why these tumors express a stable epithelial-to-mesenchymal transition phenotype, or what are the driving forces of this disease. Here, we report that Manic Fringe (Mfng), which encodes an O-fucosylpeptide 3-β-N-acetylglucosaminyltransferase known to modify EGF repeats in the Notch extracellular domain, is highly expressed in CLBC and functions as an oncogene in this context. We show that Mfng modulates Notch activation in human and mouse CLBC cell lines, as well as in mouse mammary gland. Mfng silencing in CLBC cell lines reduced cell migration, tumorsphere formation, and in vivo tumorigenicity associated with a decrease in the stem-like cell population. Mfng deletion in the Lfng(flox/flox);MMTV-Cre mouse model, in which one-third of mammary tumors resemble human CLBC, caused a tumor subtype shift away from CLBC. We identified the phosphoinositide kinase Pik3cg as a direct transcriptional target of Mfng-facilitated RBPJκ-dependent Notch signaling. Indeed, pharmacologic inhibition of PI3Kγ in CLBC cell lines blocked migration and tumorsphere formation. Taken together, our results define Mfng as an oncogene acting through Notch-mediated induction of Pik3cg. Furthermore, they suggest that targeting PI3Kγ may prove beneficial for the treatment of CLBC subtype.
authors: Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi. State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, Hunan, China.
authors: Shubing
authors: S
authors: Zhang
authors: Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi.
authors: Wen-Cheng
authors: WC
authors: Chung
authors: Department of Medical Informatics and Clinical Epidemiology and Oregon Clinical and Translational Research Institute, Oregon Health and Science University, Portland, Oregon.
authors: Guanming
authors: G
authors: Wu
authors: Program in Developmental and Stem Cell Biology, The Hospital for Sick Children and Department of Molecular Genetics, University of Toronto, Toronto, Canada.
authors: Sean E
authors: SE
authors: Egan
authors: Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center and Louisiana Cancer Research Center, New Orleans, Louisiana.
authors: Lucio
authors: L
authors: Miele
authors: Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi. Department of Neurobiology and Anatomical Sciences, University of Mississippi Medical Center, Jackson, Mississippi. kxu@umc.edu.
authors: Keli
authors: K
authors: Xu
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000235:genetics* / Q000378:metabolism; D057167:Claudins / Q000378:metabolism*; D004790:Enzyme Induction; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005964:Glucosyltransferases; D006602:Hexosyltransferases / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008321:Mammary Glands, Animal / Q000378:metabolism; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000502:physiology; D010641:Phenotype; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D057167:Claudins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051880:Receptors, Notch; D005964:Glucosyltransferases; D006602:Hexosyltransferases; C106516:MFNG protein, human; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546760:PIK3CG protein, human