title: Constitutive NOTCH3 Signaling Promotes the Growth of Basal Breast Cancers.
abstract: Notch ligands signal through one of four receptors on neighboring cells to mediate cell-cell communication and control cell fate, proliferation, and survival. Although aberrant Notch activation has been implicated in numerous malignancies, including breast cancer, the importance of individual receptors in distinct breast cancer subtypes and the mechanisms of receptor activation remain unclear. Using a novel antibody to detect active NOTCH3, we report here that NOTCH3 signals constitutively in a panel of basal breast cancer cell lines and in more than one third of basal tumors. Selective inhibition of individual ligands revealed that this signal does not require canonical ligand induction. A NOTCH3 antagonist antibody inhibited growth of basal lines, whereas a NOTCH3 agonist antibody enhanced the transformed phenotypein vitroand in tumor xenografts. Transcriptomic analyses generated a Notch gene signature that included Notch pathway components, the oncogenec-Myc, and the mammary stem cell regulatorId4This signature drove clustering of breast cancer cell lines and tumors into the common subtypes and correlated with the basal classification. Our results highlight an unexpected ligand-independent induction mechanism and suggest that constitutive NOTCH3 signaling can drive an oncogenic program in a subset of basal breast cancers.Cancer Res; 77(6); 1439-52. ©2017 AACR.
authors.affiliation: Department of Discovery Oncology, Genentech, Inc., South San Francisco, California.
authors.forename: Lisa
authors.initials: L
authors.lastname: Choy
authors.affiliation: Department of Discovery Oncology, Genentech, Inc., South San Francisco, California.
authors.forename: Thijs J
authors.initials: TJ
authors.lastname: Hagenbeek
authors.affiliation: Department of Pathology, Genentech, Inc., South San Francisco, California.
authors.forename: Margaret
authors.initials: M
authors.lastname: Solon
authors.affiliation: Department of Pathology, Genentech, Inc., South San Francisco, California.
authors.forename: Dorothy
authors.initials: D
authors.lastname: French
authors.affiliation: Department of Translational Oncology, Genentech, Inc., South San Francisco, California.
authors.forename: David
authors.initials: D
authors.lastname: Finkle
authors.affiliation: Department of Discovery Oncology, Genentech, Inc., South San Francisco, California.
authors.forename: Amy
authors.initials: A
authors.lastname: Shelton
authors.affiliation: Department of Translational Oncology, Genentech, Inc., South San Francisco, California.
authors.forename: Rayna
authors.initials: R
authors.lastname: Venook
authors.affiliation: Department of Bioinformatics & Computational Biology, Genentech, Inc., South San Francisco, California.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Brauer
authors.affiliation: Department of Discovery Oncology, Genentech, Inc., South San Francisco, California. csiebel@gene.com.
authors.forename: Christian W
authors.initials: CW
authors.lastname: Siebel
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D018295:Neoplasms, Basal Cell / Q000378:metabolism / Q000473:pathology*; D000071656:Receptor, Notch3 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D000071656:Receptor, Notch3