Class II phosphoinositide 3-kinase C2ß 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, 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-C2ß is overexpressed in several human breast cancer cell lines and in human breast cancer specimens. Our data indicate that PI3K-C2ß regulates breast cancer cell growth in vitro and in vivo and that PI3K-C2ß expression in breast tissues is correlated with the proliferative status of the tumor. Specifically we show that downregulation of PI3K-C2ß 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-C2ß-dependent regulation of cell cycle progression and cell growth revealed that PI3K-C2ß regulates cyclin B1 protein levels through modulation of microRNA miR-449a levels. Our data further demonstrate that downregulation of PI3K-C2ß inhibits breast cancer cell invasion in vitro and breast cancer metastasis in vivo. Consistent with this, PI3K-C2ß is highly expressed in lymph-nodes metastases compared to matching primary tumors. These data demonstrate that PI3K-C2ß plays a pivotal role in breast cancer progression and in metastasis development. Our data indicate that PI3K-C2ß 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.

Abeta(1-42) modulation of Akt phosphorylation via alpha7 nAChR and NMDA receptors.

Elevated Abeta and its deposition as senile plaques are pathogenic features of Alzheimer's disease. Abeta has been shown to be toxic to neurons and to inhibit long-term potentiation yet, the intracellular signalling pathways underlying these actions are unknown. We report for the first time that acute exposure of primary mouse neurons to 400nM Abeta(1-42) increased Akt phosphorylation in an alpha(7) nicotinic receptor and NMDA receptor dependant manner. However, prolonged incubation resulted in Akt phosphorylation returning to baseline consistent with the action of a physiological regulator. Analysis of an APP transgenic mouse (TAS10) revealed a significant deficit in hippocampal Akt phosphorylation at 13 months. This time point corresponds to the emergence of plaque formation and memory impairments in these mice. The present study suggests that Abeta(1-42) regulates Akt phosphorylation in a complex manner. Acutely, Abeta(1-42) stimulates Akt phosphorylation however, chronic exposure to Abeta in TAS10 mice resulted in a downregulation of Akt phosphorylation consistent with abnormalities in excitatory neurotransmission in these mice and with recent reports of Abeta(1-42) driven internalisation of NMDA receptors.