Redefining the role of FOXO in cancer

Abstract

The highly conserved Forkhead Box O (FOXO) family of transcription factors are key regulators of cellular homeostasis, proliferation, apoptosis and lifespan. FOXO transcription factors function downstream of PI3K-PKB signaling as putative tumor suppressors by repressing cell proliferation as well as stimulating apoptosis and anoikis. Conversely, FOXOs can support tumorigenesis by maintaining cellular homeostasis, stimulating metastasis and regulating therapy resistance. In line with these conflicting properties, using FOXO levels or activity as prognostic markers for cancer patient disease progression yields contradictory results. Clearly FOXOs are involved in various aspects of cancer but it remains unclear if they function as tumor suppressors or supporters. Studies dedicated to clarifying the role of FOXO in cancer therefore are essential but lacking. In this thesis we aim to address if FOXOs are tumor suppressors or tumor supporters. We do so by characterizing conditional FOXO loss, over-expression and hyper-activation in a robust orthotopic transplantation model for mouse invasive lobular carcinoma (mILC). This system allows us to determine how different levels of FOXO expression and activity affects both tumor growth and metastasis. Our studies support that FOXO3 hyper-activation suppresses tumorigenesis but unveils that FOXO loss is more detrimental to tumor growth and the metastatic capacity of mILC. We show that FOXOs support tumorigenesis by regulating cell migration, providing anoikis resistance and maintaining cellular redox homeostasis and bioenergetics. Additionally, we find that FOXOs are key regulators of the PI3K-PKB signaling feedback loop that retains PI3K-PKB activity in cancer. Based on our results we conclude that instead of being tumor suppressors FOXOs are essential for tumorigenesis albeit FOXO activity needs to be carefully tuned for tumor growth and metastasis formation. Disruption of this balance can now be pursued as a promising strategy for cancer therapy.