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Class II phosphoinositide 3-kinase C2β regulates a novel signaling pathway involved in breast cancer progression

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, m...

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Autores principales: Chikh, Anissa, Ferro, Riccardo, Abbott, Jonathan J., Piñeiro, Roberto, Buus, Richard, Iezzi, Manuela, Ricci, Francesca, Bergamaschi, Daniele, Ostano, Paola, Chiorino, Giovanna, Lattanzio, Rossano, Broggini, Massimo, Piantelli, Mauro, Maffucci, Tania, Falasca, Marco
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4951291/
https://www.ncbi.nlm.nih.gov/pubmed/26934321
http://dx.doi.org/10.18632/oncotarget.7761
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author Chikh, Anissa
Ferro, Riccardo
Abbott, Jonathan J.
Piñeiro, Roberto
Buus, Richard
Iezzi, Manuela
Ricci, Francesca
Bergamaschi, Daniele
Ostano, Paola
Chiorino, Giovanna
Lattanzio, Rossano
Broggini, Massimo
Piantelli, Mauro
Maffucci, Tania
Falasca, Marco
author_facet Chikh, Anissa
Ferro, Riccardo
Abbott, Jonathan J.
Piñeiro, Roberto
Buus, Richard
Iezzi, Manuela
Ricci, Francesca
Bergamaschi, Daniele
Ostano, Paola
Chiorino, Giovanna
Lattanzio, Rossano
Broggini, Massimo
Piantelli, Mauro
Maffucci, Tania
Falasca, Marco
author_sort Chikh, Anissa
collection PubMed
description 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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spelling pubmed-49512912016-07-21 Class II phosphoinositide 3-kinase C2β regulates a novel signaling pathway involved in breast cancer progression Chikh, Anissa Ferro, Riccardo Abbott, Jonathan J. Piñeiro, Roberto Buus, Richard Iezzi, Manuela Ricci, Francesca Bergamaschi, Daniele Ostano, Paola Chiorino, Giovanna Lattanzio, Rossano Broggini, Massimo Piantelli, Mauro Maffucci, Tania Falasca, Marco Oncotarget Research Paper 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. Impact Journals LLC 2016-02-26 /pmc/articles/PMC4951291/ /pubmed/26934321 http://dx.doi.org/10.18632/oncotarget.7761 Text en Copyright: © 2016 Chikh et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Chikh, Anissa
Ferro, Riccardo
Abbott, Jonathan J.
Piñeiro, Roberto
Buus, Richard
Iezzi, Manuela
Ricci, Francesca
Bergamaschi, Daniele
Ostano, Paola
Chiorino, Giovanna
Lattanzio, Rossano
Broggini, Massimo
Piantelli, Mauro
Maffucci, Tania
Falasca, Marco
Class II phosphoinositide 3-kinase C2β regulates a novel signaling pathway involved in breast cancer progression
title Class II phosphoinositide 3-kinase C2β regulates a novel signaling pathway involved in breast cancer progression
title_full Class II phosphoinositide 3-kinase C2β regulates a novel signaling pathway involved in breast cancer progression
title_fullStr Class II phosphoinositide 3-kinase C2β regulates a novel signaling pathway involved in breast cancer progression
title_full_unstemmed Class II phosphoinositide 3-kinase C2β regulates a novel signaling pathway involved in breast cancer progression
title_short Class II phosphoinositide 3-kinase C2β regulates a novel signaling pathway involved in breast cancer progression
title_sort class ii phosphoinositide 3-kinase c2β regulates a novel signaling pathway involved in breast cancer progression
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4951291/
https://www.ncbi.nlm.nih.gov/pubmed/26934321
http://dx.doi.org/10.18632/oncotarget.7761
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