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Class II phosphoinositide 3-kinase C2? 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-C2? is overexpressed in several human breast cancer cell lines and in human breast cancer specimens. Our data indicate that PI3K-C2? regulates breast cancer cell growth in vitro and in vivo and that PI3K-C2? expression in breast tissues is correlated with the proliferative status of the tumor. Specifically we show that downregulation of PI3K-C2? 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-C2?-dependent regulation of cell cycle progression and cell growth revealed that PI3K-C2? regulates cyclin B1 protein levels through modulation of microRNA miR-449a levels. Our data further demonstrate that downregulation of PI3K-C2? inhibits breast cancer cell invasion in vitro and breast cancer metastasis in vivo. Consistent with this, PI3K-C2? is highly expressed in lymph-nodes metastases compared to matching primary tumors. These data demonstrate that PI3K-C2? plays a pivotal role in breast cancer progression and in metastasis development. Our data indicate that PI3K-C2? 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.

SUBMITTER: Chikh A

PROVIDER: S-EPMC4951291 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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

Chikh Anissa A Ferro Riccardo R Abbott Jonathan J JJ Piñeiro Roberto R Buus Richard R Iezzi Manuela M Ricci Francesca F Bergamaschi Daniele D Ostano Paola P Chiorino Giovanna G Lattanzio Rossano R Broggini Massimo M Piantelli Mauro M Maffucci Tania T Falasca Marco M

Oncotarget 20160401 14

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 ...[more]

PMID: 26934321

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Project description:BACKGROUND:Alteration of signalling pathways regulating cell cycle progression is a common feature of cancer cells. Several drugs targeting distinct phases of the cell cycle have been developed but the inability of many of them to discriminate between normal and cancer cells has strongly limited their clinical potential because of their reduced efficacy at the concentrations used to limit adverse side effects. Mechanisms of resistance have also been described, further affecting their efficacy. Identification of novel targets that can potentiate the effect of these drugs or overcome drug resistance can provide a useful strategy to exploit the anti-cancer properties of these agents to their fullest. METHODS:The class II PI3K isoform PI3K-C2? was downregulated in prostate cancer PC3 cells and cervical cancer HeLa cells using selective siRNAs and the effect on cell growth was determined in the absence or presence of the microtubule-stabilizing agent/anti-cancer drug docetaxel. Mitosis progression was monitored by time-lapse microscopy. Clonogenic assays were performed to determine the ability of PC3 and HeLa cells to form colonies upon PI3K-C2? downregulation in the absence or presence of docetaxel. Cell multi-nucleation was assessed by immunofluorescence. Tumour growth in vivo was assessed using a xenograft model of PC3 cells upon PI3K-C2? downregulation and in combination with docetaxel. RESULTS:Downregulation of PI3K-C2? delays mitosis progression in PC3 and HeLa cells, resulting in reduced ability to form colonies in clonogenic assays in vitro. Compared to control cells, PC3 cells lacking PI3K-C2? form smaller and more compact colonies in vitro and they form tumours more slowly in vivo in the first weeks after cells implant. Stable and transient PI3K-C2? downregulation potentiates the effect of low concentrations of docetaxel on cancer cell growth. Combination of PI3K-C2? downregulation and docetaxel almost completely prevents colonies formation in clonogenic assays in vitro and strongly inhibits tumour growth in vivo. CONCLUSIONS:These data reveal a novel role for the class II PI3K PI3K-C2? during mitosis progression. Furthermore, data indicate that blockade of PI3K-C2? might represent a novel strategy to potentiate the effect of docetaxel on cancer cell growth.

Dataset Information

Class II phosphoinositide 3-kinase C2? regulates a novel signaling pathway involved in breast cancer progression.

Publications

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

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