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Abstract
IntroductionThe activation of the phosphoinositide 3-kinase (PI3K)/AKT signalling pathway is one the most frequent genetic events in breast cancer, consequently the development of PI3K inhibitors has attracted much attention. Here we evaluate the effect of PI3K inhibition on global gene expression in breast cancer cells.MethodsWe used a range of methodologies that include in silico compound analysis, in vitro kinase assays, cell invasion assays, proliferation assays, genome-wide transcription studies (Agilent Technologies full genome arrays), gene set enrichment analysis, quantitative real-time PCR, immunoblotting in addition to chromatin immunoprecipitation.ResultsWe defined the physico-chemical and the biological properties of ETP-45658, a novel potent PI3K inhibitor. We demonstrated that ETP-45658 potently inhibited cell proliferation within a broad range of human cancer cells, most potently suppressing the growth of breast cancer cells via inhibiting cell cycle. We show that this response is Forkhead box O (FOXO) protein dependent and p53 independent. Our genome-wide microarray analysis revealed that the cell cycle was the most affected biological process after exposure to ETP-45658 (or our control PI3K inhibitor PI-103), that despite the multiple transcription factors that are regulated by the PI3K/AKT signalling cascade, only the binding sites for FOXO transcription factors were significantly enriched and only a subset of all FOXO-dependent genes were induced. This disparity in gene transcription was not due to differential FOXO promoter recruitment.ConclusionsThe constitutive activation of PI3Ks and thus the exclusion of FOXO transcription factors from the nucleus is a key feature of breast cancer. Our results presented here highlight that PI3K inhibition activates specific FOXO-dependent genes that mediate cell cycle arrest in breast cancer cells.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-014-0482-y) contains supplementary material, which is available to authorized users.
Highlights
The activation of the phosphoinositide 3-kinase (PI3K)/AKT signalling pathway is one the most frequent genetic events in breast cancer, the development of phosphatidylinositol 3-kinases (PI3Ks) inhibitors has attracted much attention
Our first objective was to analyse the biological activity of ETP-45658 including the physical and chemical properties of this compound compared to the reference pan-class I PI3K and mammalian target of rapamycin (mTOR) inhibitor PI-103 [9]
Having determined the key characteristics of ETP45658, we evaluated the inhibitory activity of this compound against each member of the PI3K family, including PI3K class 1 isoforms in addition to distinct p110 mutants
Summary
The activation of the phosphoinositide 3-kinase (PI3K)/AKT signalling pathway is one the most frequent genetic events in breast cancer, the development of PI3K inhibitors has attracted much attention. The deregulation of the PI3K/AKT signalling cascade has been implicated in the deregulation of almost all the aspects of cell physiology that promotes cell transformation including cell cycle progression, enhanced chemotherapeutic resistance, elevated cell metabolism, increased resistance to hypoxia and tumour metastasis [12,13]. Many of these processes are controlled by the forkhead (FOXO) transcription family of proteins that bind to a conserved DNA motif (TTGTTTAC) driving transcription of crucial effecter proteins [14,15]. A variety of small molecules with different mechanisms of action (including pan-PI3K, dual PI3K/ mTOR, and isoform-specific PI3K inhibitors) have been developed and entered a range of clinical trials [5]
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