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Title: The role of the Runx2 in apoptosis resistance in hormone sensitive breast and prostate cancer cells
Author: Browne, Gillian
ISNI:       0000 0004 2720 6754
Awarding Body: University of Ulster
Current Institution: Ulster University
Date of Award: 2010
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Runx2 is a transcription factor widely known for its roles in skeletal development. It is recognised that its regulation and transcriptional activity are also linked to increased growth, invasion, and metastasis in various tumour types. Apoptosis resistance is one of the major hallmarks of cancer, and Bcl-2 is one of the major proteins involved in controlling apoptosis. Recent studies suggest that Runx2 is involved in apoptosis resistance. Previous work carried out in our laboratory showed an association between hypoxia and Runx2 and Bcl-2 expression in prostate tumours, and a consensus DNA binding sequence for Runx2 was found within the Bcl-2 promoter. Results from these studies formed the basis of the hypotheses of this study: The Runx2 transcription factor binds to the Bcl-2 promoter resulting in increased expression of Bcl-2 and resistance to apoptosis and that hypoxia affects the levels of Runx2 thus potentiating apoptosis resistance. Cell proliferation and apoptosis assays have shown that an increased level of Runx2 confers a survival advantage and increased resistance to apoptosis in breast and prostate cells. Protein- DNA interaction assays have suggested that Runx2 binds to and interacts with the Bcl-2 promoter. Runx2-associated apoptosis resistance has been shown to be mediated, at least in part, by increased Bcl-2 expression. mRNA expression analysis carried out has highlighted other potential targets of Runx2 which may be involved in the increased apoptosis resistance demonstrated. Investigation of the effects of acute hypoxia on Runx2 expression have established that Runx2 expression can be increased by hypoxia, and that the associated increase in survival can be diminished by silencing Runx2. However, further work is needed to substantiate these findings. Overall, the work in this thesis adds to the body of knowledge on Runx2 in cancer development and progression, demonstrating its importance in mediating apoptosis resistance in breast and prostate cancer cells. As well as presenting data to show the role of Runx2-associated increased Bcl-2 expression in this process, it also reveals novel Runx2-responsive genes potentially involved in mediating the apoptosis resistance observed. Finally, this work shows that hypoxia may be an important upstream regulator of Runx2 expression in hormone sensitive prostate cancer cells.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available