The PI3kinase/Akt pathway is frequently activated in cancer cells, leading to the cytoplasmic localisation of FoxO transcription factors and their consequent inactivation. Some of the transcriptional targets of FoxO proteins include pro-apoptotic BH3-only proteins Bim and Puma and cell cycle inhibitors p27Kip1 and p130Rb2, suggesting that loss of FoxOs should promote cell survival and proliferation. Consistent with this, combined deletion of FoxO1, 3 and 4 in haemopoietic cells has revealed they are tumour suppressors, with mice developing thymic lymphomas and haemangiomas.1 The FoxOs appear to act redundantly, as single FoxO null mice have relatively mild phenotypes. However, we hypothesized that loss of a single FoxO might cooperate in tumourigenesis when combined with deregulation of an oncogene. To test this hypothesis, we have crossed mice lacking FoxO3, a FoxO protein widely expressed in haemopoietic cells, with vavP-myc10 mice, which develop myeloid tumours, and with Eµ-myc mice, which develop pre-B and B lymphomas. The onset of tumours was accelerated by loss of FoxO3 in each of these models. We are currently investigating which of the FoxO3-regulated processes is responsible for the acceleration in tumourigenesis.
1 Paik et al., Cell 128, 309-323, 2007.