| Summary: | Despite recent advances in the treatment and detection of breast cancer it still remains the third most common cause of death from cancer in the UK as a result of its final metastatic stage, which is currently incurable. Numerous targets have been identified in an attempt to prevent and treat this highly aggressive form of cancer with limited success, however recent work has highlighted B-cell lymphoma 3 (Bcl-3) as a promising therapeutic target. Bcl-3 is a mediator of the well characterised NF-kB signalling pathway and both have been implicated with promoting tumour growth and progression. The role of Bcl-3 in mediating tumour proliferation and apoptosis has been extensively researched; however more recent work has also implicated Bcl-3 with an important role in regulating metastasis. Interestingly, suppression of Bcl-3 expression has been shown to inhibit breast cancer metastasis, a result which has been replicated through the use of small-molecule inhibitors designed to disrupt Bcl-3 binding to both p50 and p52. Despite this little is known, other than a reduction in cell motility, on how Bcl-3 is mediating its effects on metastasis, therefore the aims of this project were to elucidate the mechanisms through which Bcl-3 is regulating metastasis. In this work we have shown how Bcl-3 can regulate a variety of single-cell and collective migratory phenotypes through inhibiting Rac1 and Cdc42 GTPase activity. We have also shown for the first time Bcl-3 to be upregulated during EMT, which appears to help regulate the expression of a number of EMT-inducing genes. Interestingly, we have also shown that prolonged inhibition of Bcl-3 results in a loss of cell viability through either senescence or apoptosis which appears to be dependent on cells expressing wildtype or mutant p53 respectively. Finally we have identified a novel set of small molecule Bcl-3 inhibitors that are capable of mimicking Bcl-3 suppression to regulate human breast cancer cell lines as well as both prostate and colorectal cell lines, offering a new therapeutic option for the treatment of breast and other human cancer types.
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