Assessment of Functional Phosphatidylinositol 3-Kinase Pathway Activity in Cancer Tissue Using Forkhead Box-O Target Gene Expression in a Knowledge-Based Computational Model

The American Journal of Pathology
Henk van OoijenAnja Van de Stolpe

Abstract

The phosphatidylinositol 3-kinase (PI3K) pathway is commonly activated in cancer. Tumors are potentially sensitive to PI3K pathway inhibitors, but reliable diagnostic tests that assess functional PI3K activity are lacking. Because PI3K pathway activity negatively regulates forkhead box-O (FOXO) transcription factor activity, FOXO target gene expression is inversely correlated with PI3K activity. A knowledge-based Bayesian computational model was developed to infer PI3K activity in cancer tissue samples from FOXO target gene mRNA levels and validated in cancer cell lines treated with PI3K inhibitors. However, applied to patient tissue samples, FOXO was often active in cancer types with expected active PI3K. SOD2 was differentially expressed between FOXO-active healthy and cancer tissue samples, indicating that cancer-associated cellular oxidative stress alternatively activated FOXO. To enable correct interpretation of active FOXO in cancer tissue, threshold levels for normal SOD2 expression in healthy tissue were defined above which FOXO activity is oxidative stress induced and below which PI3K regulated. In slow-growing luminal A breast cancer and low Gleason score prostate cancer, FOXO was active in a PI3K-regulated manner, in...Continue Reading

Citations

Apr 6, 2019·Interactive Journal of Medical Research·Michael van HartskampAnja van de Stolpe
Jun 9, 2020·British Journal of Cancer·Willem Jan van WeeldenJohanna M A Pijnenborg
Nov 17, 2020·Frontiers in Immunology·Wilbert BouwmanAnja van de Stolpe
Sep 12, 2020·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Konrad H StopsackMassimo Loda
Nov 19, 2020·Journal of Fluorescence·Freek van HemertAnja van de Stolpe
Oct 31, 2020·Cancers·Kirsten Canté-BarrettJules P P Meijerink
May 22, 2021·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Rachel BleachMarie McIlroy
Dec 11, 2021·Frontiers in Medicine·Wilbert BouwmanAnja van de Stolpe

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