title: Notch reporter activity in breast cancer cell lines identifies a subset of cells with stem cell activity.
abstract: Developmental pathways such as Notch play a pivotal role in tissue-specific stem cell self-renewal as well as in tumor development. However, the role of Notch signaling in breast cancer stem cells (CSC) remains to be determined. We utilized a lentiviral Notch reporter system to identify a subset of cells with a higher Notch activity (Notch(+)) or reduced activity (Notch(-)) in multiple breast cancer cell lines. Using in vitro and mouse xenotransplantation assays, we investigated the role of the Notch pathway in breast CSC regulation. Breast cancer cells with increased Notch activity displayed increased sphere formation as well as expression of breast CSC markers. Interestingly Notch(+) cells displayed higher Notch4 expression in both basal and luminal breast cancer cell lines. Moreover, Notch(+) cells demonstrated tumor initiation capacity at serial dilutions in mouse xenografts, whereas Notch(-) cells failed to generate tumors. γ-Secretase inhibitor (GSI), a Notch blocker but not a chemotherapeutic agent, effectively targets these Notch(+) cells in vitro and in mouse xenografts. Furthermore, elevated Notch4 and Hey1 expression in primary patient samples correlated with poor patient survival. Our study revealed a molecular mechanism for the role of Notch-mediated regulation of breast CSCs and provided a compelling rationale for CSC-targeted therapeutics.
authors: Rosemarie C
authors: RC
authors: D'Angelo
authors: Maria
authors: M
authors: Ouzounova
authors: April
authors: A
authors: Davis
authors: Georgia Regents University Cancer Center, Department of Biochemistry and Molecular Biology 1410 Laney Walker Blvd. CN2136 Augusta, GA 30912.
authors: Daejin
authors: D
authors: Choi
authors: Georgia Regents University Cancer Center, Department of Biochemistry and Molecular Biology 1410 Laney Walker Blvd. CN2136 Augusta, GA 30912.
authors: Stevie M
authors: SM
authors: Tchuenkam
authors: Gwangil
authors: G
authors: Kim
authors: Tahra
authors: T
authors: Luther
authors: Ahmed A
authors: AA
authors: Quraishi
authors: Yasin
authors: Y
authors: Senbabaoglu
authors: Sarah J
authors: SJ
authors: Conley
authors: Shawn G
authors: SG
authors: Clouthier
authors: Khaled A
authors: KA
authors: Hassan
authors: Max S
authors: MS
authors: Wicha
authors: Hasan
authors: H
authors: Korkaya
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D064593:Heterografts; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D053829:Amyloid Precursor Protein Secretases; D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D051880:Receptors, Notch; D012097:Repressor Proteins; C405694:Hairy, HRT1 protein