How are meiotic genes re-activated in cancer and can we exploit this in the clinic?

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Under normal circumstances, reproductive proteins make sure that a baby receives half of its genetic material, DNA, from the mother (through the egg) and half from the father (through the sperm). This means that the baby contains a mixture of both their mother's and father's genes. Reproductive proteins are believed to be present only in organs that take part in reproduction and have no other known roles in the body.Unexpectedly, we recently discovered that some of these reproductive proteins, known as 'SC proteins', are also found in cancer cells. Furthermore, when the levels of SC proteins are high, patients have a more aggressive disease and die earlier. Currently, we do not understand why and how cancer cells make these reproductive proteins. However, we have observed that chemotherapies used to treat certain cancers can cause reproductive factors to turn back on. This, in turn, can lead to therapy resistance and worsening of the cancer. Our goal is to determine how SC proteins are switched back on in cancer, and which chemotherapies cause the proteins to be switched on. We will address these questions through three pieces of work, each with specific aims.Aim 1. Characterise promoter binding proteins responsible for SC promoter production in cancer.Production of a protein inside a cell is triggered by activating proteins - promoter binding proteins - interacting with the DNA which encodes the protein. Cells have a wide range of promoter binding proteins. We will use a novel approach developed in my lab to discover which promoter binding proteins interact with DNA encoding SC proteins and activate protein production.Aim 2. Characterise the network of regulators involved in SC re-expression in cancer.It is essential that the correct promoter binding proteins are active at the right time. The availability of each type of promoter binding protein is controlled by a network of other proteins. This network of proteins can therefore indirectly affect whether SC proteins are made in cancer cells. In this section of work we will use a combination of laboratory and computational experiments to characterise the protein networks responsible for SC protein production. Aim 3. Determine which anti-cancer therapeutics activate SC expression and the impact this has on treatment outcome.Finally, we will perform experiments analysing the levels of SC proteins produced in cancer cells in the presence of a range of commonly-used anti-cancer therapies. We will identify therapies that cause SC proteins to be made in cancer cells, and also establish the impact SC protein production has on resistance development.Our project has important implications for future cancer treatment. Currently, more than 166,000 people die from cancer in the UK each year. Becoming resistant to chemotherapy and the resulting treatment failure is responsible for 90% of these deaths. Our research will help to identify those whose cancers are becoming treatment resistant and - in the longer term - paves the way for new drugs to prevent resistance developing.In addition, one of the main challenges in cancer treatment is to selectively kill tumour cells whilst sparing healthy cells. Unfortunately, most anti-cancer treatments also kill healthy cells, which is the reason for side-effects like nausea and weakness. As reproductive proteins are absent in normal healthy organs, they could be important new targets for the development of anti-cancer drugs. Killing cancer cells that express these proteins might be specific, and protect healthy non-cancer cells, resulting in less side-effects for patients.