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Title: Role of the FOXO-FOXM1 axis in the progression of metastatic breast cancer
Author: Bella, Laura
ISNI:       0000 0004 7657 1854
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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Lack of available therapies to combat and prevent tumour progression have rendered tumour metastasis one of the primary causes of mortality in cancer. Interestingly, the insurgence of tumour resistance to cytotoxic chemotherapy has been linked to tumour relapse and death. This project aimed to characterise the phenotypical and behavioural alteration that breast cancer cell lines adopt when developing resistance to the anthracycline (epirubicin) and the taxane (paclitaxel). It then aimed to associate these alterations with varying levels of the Forkhead Box proteins FOXO-FOXM1 expression, to determine whether these transcription factors, extensively characterised for their role in both the development of drug resistance and individual aspects of cancer progression, could cause the changes noted in these cell lines. Using a combination of in vitro techniques and the novel in vivo zebrafish embryo model, developed during this project, the drug resistant MCF-7 breast cancer cell lines were shown to have undergone the epithelial to mesenchymal transition and possess significantly increased capacities to migrate and form mammospheres in vitro as well as induce neoangiogenesis and metastasize in vivo, when compared with their parental MCF-7 WT cells. More in depth analysis demonstrated FOXO3 endogenous suppression was key to the loss of E-cadherin expression, whilst the overexpression of FOXM1 could be directly linked to the increased cancer progression capacities noted in the resistant cell lines. Then, KIF20A was identified as a critical FOXM1 down-stream effector that could regulate all aspects of cancer progression through a hypothesized structural interaction with the cytoskeleton. Alternatively, SOX4 was shown to possess a completely novel angiogenic function, which could, when inhibited, completely prevent breast cancer induced angiogenesis in vivo. In conclusion, this project unveiled a novel rate-limiting role for FOXO-FOXM1, as well as KIF20A and SOX4 as prognostic markers and potential drug targets to combat the cancer progression of breast cancer.
Supervisor: Lam, Eric W. F. ; Bugeon, Laurence Sponsor: Breast Cancer Now
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral