ArticleBreast cancer research : BCR2014
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.
Article in Breast cancer research : BCR, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 41 citations in OpenAlex.
- Insulin receptor substrate 2 (IRS2) confers resistance to PI3K pathway inhibition in PIK3CA mutant breast cancer.The Journal of biological chemistry · 2026Article
- Chronic psychological stress disrupts liver homeostasis by dysregulating oxidative phosphorylation via the PI3K/AKT/FoxO3a axis.iScience · 2026Article
- Longitudinal host-microbiome dynamics of metatranscription identify hallmarks of progression in periodontitis.Microbiome · 2025Article
- Carotenoids Modulate FoxO-Induced Cell Cycle Awrrest in Human Cancer Cell Lines: A Scoping Review.Food science & nutrition · 2025Article
- The Biological Roles and Clinical Applications of the PI3K/AKT Pathway in Targeted Therapy Resistance in HER2-Positive Breast Cancer: A Comprehensive Review.International journal of molecular sciences · 2024Review
- A non-canonical role of somatic Cyclin D/CYD-1 in oogenesis and in maintenance of reproductive fidelity, dependent on the FOXO/DAF-16 activation state.PLoS genetics · 2024Article
- Translational Relevance of Secondary Intracellular Signaling Cascades Following Traumatic Spinal Cord Injury.International journal of molecular sciences · 2024Review
- Klotho inhibits IGF1R/PI3K/AKT signalling pathway and protects the heart from oxidative stress during ischemia/reperfusion injury.Scientific reports · 2023Article
- Genes That Extend Lifespan May Do So by Mitigating the Increased Risk of Death Posed by Having Hypertension.American journal of hypertension · 2023Article
- FOXO family isoforms.Cell death & disease · 2023Review
- Role of Fork-Head Box Genes in Breast Cancer: From Drug Resistance to Therapeutic Targets.Biomedicines · 2023Review
- Multiplexed cellular profiling identifies an organoselenium compound as an inhibitor of CRM1-mediated nuclear export.Traffic (Copenhagen, Denmark) · 2022Article
- The Impact of Oxidative Stress and AKT Pathway on Cancer Cell Functions and Its Application to Natural Products.Antioxidants (Basel, Switzerland) · 2022Review
- Article
- Therapeutic strategies targeting FOXO transcription factors.Nature reviews. Drug discovery · 2021Review
- FOXO1: a pivotal pioneer factor in oral squamous cell carcinoma.American journal of cancer research · 2021Review
- NVP-BEZ235 or JAKi Treatment leads to decreased survival of examined GBM and BBC cells.Cancer treatment and research communications · 2021Article
- Article
- In silico authentication of amygdalin as a potent anticancer compound in the bitter kernels of family Rosaceae.Saudi journal of biological sciences · 2020Article
- Article
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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