The role and regulation of FOXO3a in cancer and chemotherapy resistance

• Main Author: Gomes, Ana Rita
• Other Authors: Lam, Eric
• Published: Imperial College London 2012
• Subjects: 610
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.616712

Drug resistance is the major impediment to the success of cancer therapy. The PI3K/AKT pathway mediates a plethora of cellular functions, including cell survival, proliferation and differentiation. However, increased activation of this pathway has been correlated with drug resistance mechanisms. This pathway regulates the activity of FOXO transcription factors in a negative manner through AKT-dependent phosphorylations. The modulation of FOXO activity leads to a variety of cellular outputs, including cell cycle arrest and apoptosis that define this transcription factor as a tumour suppressor. Importantly, FOXO has also been shown to mediate the effect of many anti-cancer drugs, suggesting that it has an additional role in drug sensitivity and resistance. With this work, by studying the PI3K/AKT/FOXO axis in breast cancer, I have characterised its impact in drug sensitivity and resistance. I found that this axis is deregulated in breast cancer resistant cells. By extending my in vitro findings to clinical samples, I further elucidated the potential role of AKT and FOXO3a as indicators and predictors of treatment response in breast cancer. In addition, I have also characterised three novel downstream targets of FOXO3a - FOXP1, FOXM1 and VEGF – with important roles towards breast cancer progression and in the development of drug-resistance. By characterising these FOXO3a effectors, I unravelled a potential general mechanism by which FOXO3a represses gene target expression.