A novel phosphatidylinositol 3-kinase PI3K inhibitor directs a potent FOXO-dependent, p53-independent cell cycle arrest phenotype characterized by the differential induction of a subset of FOXO-regulated genesReport as inadecuate




A novel phosphatidylinositol 3-kinase PI3K inhibitor directs a potent FOXO-dependent, p53-independent cell cycle arrest phenotype characterized by the differential induction of a subset of FOXO-regulated genes - Download this document for free, or read online. Document in PDF available to download.

Breast Cancer Research

, 16:482

First Online: 09 December 2014Received: 26 July 2014Accepted: 14 November 2014DOI: 10.1186-s13058-014-0482-y

Cite this article as: Hill, R., Kalathur, R.K.R., Callejas, S. et al. Breast Cancer Res 2014 16: 482. doi:10.1186-s13058-014-0482-y

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.

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