Grant: Operating Grant

Many cancers are caused by the abnormal production of normal or mutated proteins from our genes. An important means that determines which proteins are made by our cells occurs just before the last step in protein production, when the 'messenger' intermediates of genes are read by the machinery that makes proteins. We have discovered mutations in an enzyme called Dicer that normally produces cellular components that block these messengers thus reducing protein production (published in the New England Journal of Medicine, 2012). In tumours with Dicer mutations the products of Dicer are not made causing the protein building machinery to make proteins they shouldn't. This novel mechanism leads to protein changes that eventually cause cells to become cancerous. While we first found these mutations of Dicer in rare ovarian cancers we have also recently identified these Dicer mutations in uterine cancers, and Dicer is known to be involved in the development of other more common non-ovarian cancers. Therefore, studying the rare cancer mutations will help resolve the many conflicting theories about how Dicer contributes to cancer. Our research will study how Dicer mutations we found affect the behaviour of Dicer, and how Dicer helps determine which proteins are made in a cell. These studies will be performed in both cells and test tube experiments by changing the structure of Dicer and measuring changes in the protein making machinery, the gene-messenger intermediates changed by this machinery, and the proteins that are finally made. From our studies we hope to expose treatment strategies specialized for ovarian and other cancers with Dicer mutations. Our results could also have a much broader impact as changes in the amount of Dicer in a cancer cell, either too much or too little, are often reported. We hope increasing our knowledge on how Dicer controls production of specific proteins that could lead to cancer will lead to more generalisable treatment opportunities.