The RNA helicase p68 (DDX5) as a selective modulator of the p53 response to chemotherapy

Breast cancer patients who are treated with chemotherapy show a huge variability in their response. Chemotherapy often results in undesirable side effects that can reduce quality of life and lead to life threating complications. Therefore, identifying patients who will benefit from chemotherapy remains a major research challenge. The p53 tumour suppressor plays a key role in the response to chemotherapy and is frequently mutated in many cancers. However, contrary to expectations, in breast cancer, 70% of which harbour wild type p53, the presence of wt p53 appears to result in an impaired response to chemotherapy, allowing some cancer cells to survive.
Several factors influence the biological outcome of p53 activation by DNA damage (e.g. by chemotherapy), the mechanisms governing the choice between cell cycle arrest and apoptosis remain to be elucidated. We have previously demonstrated that p68 is a potent activator of p53 and is selectively required for p53-mediated transactivation of the cell cycle arrest gene p21WAF1 in response to DNA damage in vitro and in vivo [1, 2]. Our findings thus highlight a novel function of p68 as a selective regulator of the p53 DNA damage response and demonstrate that it can modulate the decision between cell cycle arrest and apoptosis in a context-dependent manner. Furthermore, our very recent data indicate that p68 is required for p53-mediated survival of cells treated with chemotherapeutic drugs, providing a possible mechanism by which tumour cells harbouring wild type p53 could impair the response of cancers to chemotherapeutic agents.
The proposed project aims to explore the mechanism(s) by which p68 mediates p53-dependent resistance to chemotherapy in breast cancer. In the longer term, data from this project may not only allow the identification of patients who are more likely to benefit from chemotherapy but may also lead to the possibility of additionally targeting p68 in breast cancer to increase the efficacy of chemotherapeutic strategies. The project will employ a range of molecular and cell biology techniques and will also provide the opportunity to study p68/p53 and p21 expression in primary tumour tissues.