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Title: Regulation of FoxO transcription factors in breast cancer
Author: Pomeranz, Karen M.
ISNI:       0000 0004 2668 6100
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2008
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Breast cancer is the world's most prevalent cancer. Although several drugs and chemotherapeutic strategies have been developed to tackle breast cancer, to date most patients eventually acquire resistance to these anticancer therapies. Therefore, identifying ways to increase the efficiency of currently used chemotherapeutic drugs and the development of new drugs for breast cancer treatment is essential. One way to achieve this goal is by identifying cellular targets which play a pivotal role in tumourigenesis and tumour progression. Paclitaxel belongs to a class of naturally occurring anti microtubule agents used for the treatment of malignancies such as breast cancer. Previous work has shown that FoxO3a, a transcription factor downstream of the phosphotidylinsitol-3-kinase/Akt signalling pathway, mediates apoptosis and cell cycle arrest in breast cancer cells in response to paclitaxel treatment. In order to elucidate the significance of FoxO expression and activation in response to paclitaxel treatment and oxidative stress (which is caused by paclitaxel treatment), I investigated the regulation of FoxO in endometrial and breast cancer cells. Both paclitaxel and oxidative stress were found to upregulate FoxO expression at the protein, mRNA and gene-promoter levels. Moreover, treatment with paclitaxel and hydrogen peroxide were shown to increase FoxO3a protein stability. Paclitaxel treatment resulted in JNK mediated nuclear accumulation of FoxO3a with a corresponding reduction in Akt activity. JNK was also shown to induce FoxO3a gene-promoter activity and to phosphorylate FoxO3a at two sites. These phosphorylation events may be important in the regulation of FoxO3a stability and activity. I also investigated the function of FoxO3a, by studying the role of BTG1, a downstream target of FoxO3a. I found that BTG1 expression was induced at the gene-promoter level by FoxO3a in MCF-7 cells. The use of a BTG1 inducible MCF-7 cell line revealed that over-expression of BTG1 results in changes in the expression levels of cell cycle regulators, reduction in cell growth and accumulation of cells in the G2/M phase of the cell cycle. Taken together, these results show that FoxO expression and activity are upregulated following paclitaxel treatment and demonstrate that the PI3K/Akt/FoxO and JNK signalling pathways cross-talk at least at two levels. Furthermore, these results indicate that FoxO expression levels may serve as bio-marker for determining the effectiveness of paclitaxel treatment of breast cancer patients and that FoxOs may serve as a potential target for anti-cancer chemotherapeutic intervention.
Supervisor: Lam, Eric ; Coombes, Charles Sponsor: Westminster Oncology Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral