AbstractBreast cancer is the leading cause of cancer death in women worldwide. Although significant advances have been made in the treatment of breast cancer, new therapeutic approaches are required. Protein synthesis is often found to be deregulated in cancer and there has been significant effort into developing strategies to inhibit protein synthesis for anti-cancer therapeutics. The addition of the 7-methylguanosine cap (methyl cap) at the 5’ end of mRNA is essential for efficient protein synthesis and cell viability. In humans, RNA guanine-7 methyltransferase (RNMT) methylates the guanosine cap. RNMT expression is essential for cell viability and efficient gene expression.
This thesis demonstrates that a subset of breast cancer cells exhibit an enhanced dependence on RNMT for survival, in comparison to immortalised mammary epithelial cells. Moreover, RNMT depletion induces apoptosis in a subset of breast cancer cell lines. Further analyses reveal that this cellular sensitivity to RNMT depletion does not correlate with cellular RNMT expression, RNMT enzymatic activity, global protein synthesis levels, basal cell proliferation rate or c-Myc protein expression. It was found that activating mutations in the gene PIK3CA, which encodes the p110α catalytic subunit of PI3K, contributes to cellular RNMT dependency. Moreover, inhibition of PI3K signalling in a RNMT depletion sensitive breast cancer cell line reverses the sensitivity. These findings provide the first evidence that RNMT dependency in breast cancer is related to PI3K activity/ signalling. Since an estimated 18-40% of breast tumours have activating mutations in PIK3CA, my findings could potentially have significant therapeutic implications.
|Date of Award||2014|
|Supervisor||Victoria Cowling (Supervisor)|