The regulation of FOXM1 in breast cancer
File(s)
Author(s)
Kongsema, Mesayamas
Type
Thesis
Abstract
Breast cancer is the most commonly diagnosed cancer in women worldwide. In the UK,
there is 1 in 8 of women that have a risk of being diagnosed with breast cancer in a
lifetime. Clinically, the common treatment using for breast cancer therapy are
combinations of surgery, radiotherapy, endocrinal (hormonal) therapy and
chemotherapy. The DNA damaging agent epirubicin has been shown to be an effective
chemotherapeutic drug for breast cancer treatment. Nevertheless, there are more than
90% of patients with metastatic cancer that found to be resistant to the drug.
FOXM1 is a transcription factor that has been reported to be responsible for a
resistance to various chemotherapeutics, including epirubicin. Accumulating evidence
has revealed that FOXM1 is regulated by modifications at the post-translational levels.
In this study, I show that FOXM1 can also be regulated by SUMOylation and
ubiquitination. In response to epirubicin treatment, FOXM1 is modified primarily by
SUMO1, and not SUMO2/3, in breast cancer cells. The SUMOylation of FOXM1 is
targeted by RNF168 and leads to its ubiquitination, nuclear exportation and degradation
through the proteasome degradation pathway. Unfortunately, the study about OTUB1
about its property in deubiquitinating ubiquitinated FOXM1 does not show the significant
results. Collectively, this thesis identifies and characterises the role of SUMOylation,
ubiquitination and RNF168 in modulating FOXM1 expression and activity, by promoting
its degradation. My data suggest that these proteins and PTMs might be interesting
targets for the development of novel therapeutic strategies for breast cancer treatment
and for overcoming conventional chemotherapeutic drug resistance.
there is 1 in 8 of women that have a risk of being diagnosed with breast cancer in a
lifetime. Clinically, the common treatment using for breast cancer therapy are
combinations of surgery, radiotherapy, endocrinal (hormonal) therapy and
chemotherapy. The DNA damaging agent epirubicin has been shown to be an effective
chemotherapeutic drug for breast cancer treatment. Nevertheless, there are more than
90% of patients with metastatic cancer that found to be resistant to the drug.
FOXM1 is a transcription factor that has been reported to be responsible for a
resistance to various chemotherapeutics, including epirubicin. Accumulating evidence
has revealed that FOXM1 is regulated by modifications at the post-translational levels.
In this study, I show that FOXM1 can also be regulated by SUMOylation and
ubiquitination. In response to epirubicin treatment, FOXM1 is modified primarily by
SUMO1, and not SUMO2/3, in breast cancer cells. The SUMOylation of FOXM1 is
targeted by RNF168 and leads to its ubiquitination, nuclear exportation and degradation
through the proteasome degradation pathway. Unfortunately, the study about OTUB1
about its property in deubiquitinating ubiquitinated FOXM1 does not show the significant
results. Collectively, this thesis identifies and characterises the role of SUMOylation,
ubiquitination and RNF168 in modulating FOXM1 expression and activity, by promoting
its degradation. My data suggest that these proteins and PTMs might be interesting
targets for the development of novel therapeutic strategies for breast cancer treatment
and for overcoming conventional chemotherapeutic drug resistance.
Version
Open Access
Date Issued
2014-10
Date Awarded
2015-02
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Lam, Eric
Sponsor
Thailand
Publisher Department
Department of Surgery & Cancer
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)