Class II phosphoinositide 3-kinase C2β regulates a novel signaling pathway involved in breast cancer progression
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Anissa Chikh1,*, Riccardo Ferro1,*, Jonathan J. Abbott1, Roberto Piñeiro1, Richard Buus1, Manuela Iezzi3, Francesca Ricci4, Daniele Bergamaschi1, Paola Ostano5, Giovanna Chiorino5, Rossano Lattanzio2,3, Massimo Broggini4, Mauro Piantelli2,3, Tania Maffucci1 and Marco Falasca1,6
1 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
2 Department of Medical, Oral and Biotechnological Sciences, University “G. d’Annunzio”, Chieti, Italy
3 Aging Research Centre (Ce.S.I.), Foundation University “G. d’Annunzio”, Chieti, Italy
4 Laboratory of Molecular Pharmacology IRCCS-Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, Italy
5 Cancer Genomics Laboratory, Fondazione Edo and Elvo Tempia, Biella, Italy
6 Metabolic Signalling Group, School of Biomedical Sciences, CHIRI Biosciences, Curtin University, Perth, Western Australia, Australia
* These authors have contributed equally to this work
Marco Falasca, email:
Keywords: breast cancer, cyclinB1, metastasis, miR449, phosphoinositide 3-kinase C2β
Received: February 04, 2016 Accepted: February 11, 2016 Published: February 26, 2016
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.
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