The role and regulation of FOXO3a in cancer and chemotherapy resistance
Author(s)
Gomes, Ana Rita
Type
Thesis
Abstract
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.
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.
Date Issued
2011
Date Awarded
2012-04
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Lam, Eric
Publisher Department
Surgery and Cancer
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)