title: Class II phosphoinositide 3-kinase C2β regulates a novel signaling pathway involved in breast cancer progression.
abstract: It is now well established that the enzymes phosphoinositide 3-kinases (PI3Ks) have a key role in the development and progression of many cancer types and indeed PI3Ks inhibitors are currently being tested in clinical trials. Although eight distinct PI3K isoforms exist, grouped into three classes, most of the evidence currently available are focused on one specific isoform with very little known about the potential role of the other members of this family in cancer. Here we demonstrate that the class II enzyme PI3K-C2β is overexpressed in several human breast cancer cell lines and in human breast cancer specimens. Our data indicate that PI3K-C2β regulates breast cancer cell growth in vitro and in vivo and that PI3K-C2β expression in breast tissues is correlated with the proliferative status of the tumor. Specifically we show that downregulation of PI3K-C2β in breast cancer cell lines reduces colony formation, induces cell cycle arrest and inhibits tumor growth, in particular in an estrogen-dependent in vivo xenograft. Investigation of the mechanism of the PI3K-C2β-dependent regulation of cell cycle progression and cell growth revealed that PI3K-C2β regulates cyclin B1 protein levels through modulation of microRNA miR-449a levels. Our data further demonstrate that downregulation of PI3K-C2β inhibits breast cancer cell invasion in vitro and breast cancer metastasis in vivo. Consistent with this, PI3K-C2β is highly expressed in lymph-nodes metastases compared to matching primary tumors. These data demonstrate that PI3K-C2β plays a pivotal role in breast cancer progression and in metastasis development. Our data indicate that PI3K-C2β may represent a key molecular switch that regulates a rate-limiting step in breast tumor progression and therefore it may be targeted to limit breast cancer spread.
authors.affiliation: Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Blizard Institute, Centre for Cell Biology and Cutaneous Research, London, UK.
authors.forename: Anissa
authors.initials: A
authors.lastname: Chikh
authors.affiliation: Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Blizard Institute, Centre for Cell Biology and Cutaneous Research, London, UK.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Ferro
authors.affiliation: Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Blizard Institute, Centre for Cell Biology and Cutaneous Research, London, UK.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Abbott
authors.affiliation: Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Blizard Institute, Centre for Cell Biology and Cutaneous Research, London, UK.
authors.forename: Roberto
authors.initials: R
authors.lastname: Piñeiro
authors.affiliation: Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Blizard Institute, Centre for Cell Biology and Cutaneous Research, London, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Buus
authors.affiliation: Aging Research Centre (Ce.S.I.), Foundation University "G. d'Annunzio", Chieti, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Iezzi
authors.affiliation: Laboratory of Molecular Pharmacology IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Ricci
authors.affiliation: Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Blizard Institute, Centre for Cell Biology and Cutaneous Research, London, UK.
authors.forename: Daniele
authors.initials: D
authors.lastname: Bergamaschi
authors.affiliation: Cancer Genomics Laboratory, Fondazione Edo and Elvo Tempia, Biella, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Ostano
authors.affiliation: Cancer Genomics Laboratory, Fondazione Edo and Elvo Tempia, Biella, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Chiorino
authors.affiliation: Aging Research Centre (Ce.S.I.), Foundation University "G. d'Annunzio", Chieti, Italy.|Department of Medical, Oral and Biotechnological Sciences, University "G. d'Annunzio", Chieti, Italy.
authors.forename: Rossano
authors.initials: R
authors.lastname: Lattanzio
authors.affiliation: Laboratory of Molecular Pharmacology IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Broggini
authors.affiliation: Aging Research Centre (Ce.S.I.), Foundation University "G. d'Annunzio", Chieti, Italy.|Department of Medical, Oral and Biotechnological Sciences, University "G. d'Annunzio", Chieti, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Piantelli
authors.affiliation: Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Blizard Institute, Centre for Cell Biology and Cutaneous Research, London, UK.
authors.forename: Tania
authors.initials: T
authors.lastname: Maffucci
authors.affiliation: Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Blizard Institute, Centre for Cell Biology and Cutaneous Research, London, UK.|Metabolic Signalling Group, School of Biomedical Sciences, CHIRI Biosciences, Curtin University, Perth, Western Australia, Australia.
authors.forename: Marco
authors.initials: M
authors.lastname: Falasca
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D058541:Class II Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D064593:Heterografts; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D015398:Signal Transduction
chemical_list: D058541:Class II Phosphatidylinositol 3-Kinases; C502616:PIK3C2B protein, human
keywords: breast cancer; cyclinB1; metastasis; miR449; phosphoinositide 3-kinase C2β