title: An integrated genomic approach identifies that the PI3K/AKT/FOXO pathway is involved in breast cancer tumor initiation.
abstract: Therapy resistance is one of the major impediments to successful cancer treatment. In breast cancer, a small subpopulation of cells with stem cell features, named breast cancer stem cells (BCSC), is responsible for metastasis and recurrence of the tumor. BCSC have the unique ability to grow under non-adherent conditions in "mammospheres". To prevent breast cancer recurrence and metastasis it will be crucial to eradicate BCSC.We used shRNA genetic screening to identify genes that upon knockdown enhance mammosphere formation in breast cancer cells. By integration of these results with gene expression profiles of mammospheres and NOTCH-activated cells, we identified FOXO3A. Modulation of FOXO3A activity results in a change in mammosphere formation, expression of mammary stem cell markers and breast cancer initiating potential. Importantly, lack of FOXO3A expression in breast cancer patients is associated with increased recurrence rate. Our findings provide evidence for a role for FOXO3A downstream of NOTCH and AKT that may have implications for therapies targeting BCSCs.
authors.affiliation: Division of Molecular Carcinogenesis and Cancer Genomics Center Netherlands, The Netherlands Cancer Institute, Plesmanlaan, CX, Amsterdam, The Netherlands.|Department of Hematology, VU University Medical Center, Cancer Center Amsterdam, De Boelelaan, Amsterdam, The Netherlands.
authors.forename: Linda
authors.initials: L
authors.lastname: Smit
authors.affiliation: Division of Molecular Carcinogenesis and Cancer Genomics Center Netherlands, The Netherlands Cancer Institute, Plesmanlaan, CX, Amsterdam, The Netherlands.
authors.forename: Katrien
authors.initials: K
authors.lastname: Berns
authors.affiliation: Breast Biology Group, Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester, Manchester, UK.
authors.forename: Katherine
authors.initials: K
authors.lastname: Spence
authors.affiliation: Department of Medical Statistics, The Christie NHS Trust, Manchester, UK.
authors.forename: W David
authors.initials: WD
authors.lastname: Ryder
authors.affiliation: St John of God Subiaco Hospital, Subiaco, Perth, WA, Australia.
authors.forename: Nik
authors.initials: N
authors.lastname: Zeps
authors.affiliation: Division of Molecular Carcinogenesis and Cancer Genomics Center Netherlands, The Netherlands Cancer Institute, Plesmanlaan, CX, Amsterdam, The Netherlands.
authors.forename: Mandy
authors.initials: M
authors.lastname: Madiredjo
authors.affiliation: Division of Molecular Carcinogenesis and Cancer Genomics Center Netherlands, The Netherlands Cancer Institute, Plesmanlaan, CX, Amsterdam, The Netherlands.
authors.forename: Roderick
authors.initials: R
authors.lastname: Beijersbergen
authors.affiliation: Division of Molecular Carcinogenesis and Cancer Genomics Center Netherlands, The Netherlands Cancer Institute, Plesmanlaan, CX, Amsterdam, The Netherlands.
authors.forename: René
authors.initials: R
authors.lastname: Bernards
authors.affiliation: Breast Biology Group, Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester, Manchester, UK.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Clarke
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D005260:Female; D000071316:Forkhead Box Protein O3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D006801:Humans; D042361:Mammary Glands, Human / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: AKT; FOXO; breast cancer; genetic screen; stem cells