Transcriptional responses to pathways: roles in the causes and treatment of cancer
Intra-cellular stress-response pathways are activated in response to potentially deleterious conditions in the cell’s environment. In single celled organisms these pathways are generally involved in ensuring the survival and replication of the individual cell. In complex multi-cellular organisms such as man, they are critical in maintaining the normal function of each organ in the body, and the survival of the organism as a whole. Stress-response pathways play a key role in the patho-physiology and treatment of many diseases, including cancer.At almost every stage of the development of a tumour, cells are exposed to some form of stress. Examples include exposure to toxic compounds or radiation, loss of contact with other cells or the extra-cellular matrix, lack of oxygen (hypoxia), acidic pH, the activation of oncogenes, induction of cellular senescence, oxidative damage or depletion of essential metabolites. In some circumstances, the activation of a stress-response pathway will actually help the tumour cell to survive and proliferate. In other situations the response is cell cycle arrest or programmed cell death (apoptosis), providing a barrier to further tumour development that the tumour may ultimately circumvent through the acquisition of a mutation in one of the genes within the stress-response pathway. The p53 tumour suppressor protein is a key component of one such stress-response pathway, and virtually all cancers loose functionality of the p53-stress response pathway. Many current and prospective treatments for cancer work by either inhibiting, or re-activating stress response pathways.Our work focuses on the role of regulators of gene transcription in the response of cancer cells to stress. We have a long-standing interest in the p53 protein, a stress-activated transcriptional activator. We have also developed interests in other pathways which regulate gene transcription and cancer cell proliferation in response to stress and changes in cell metabolism. We aim to determine the role of these pathways in the development of cancer, and establish the potential for targeting components of the pathways for cancer therapy.Our group is based in the purpose-built Somers Cancer Research Building. Modern, well equipped laboratories provide us with an excellent research environment, and the opportunity to interact with researchers working on related areas of cancer biology.
Some Example Projects:
Regulation of HDM2 and HDMX proteins
The HDM2 oncoprotein is the major negative regulator of p53 function in the cell. In the late 1990s work from a number of groups, including Blaydes et al , demonstrated that HDM2 could be targeted in cancer cells to re-activate the p53 stress-response pathway. Subsequently, small molecule inhibitors of HDM2 have been developed that show great promise in pre-clinical trials. We have undertaken a series of projects examining how HDM2, and its paralogue HDMX is regulated in cancer cells (see Phillips et al, 2010, 2008, 2007, 2006a, 2006b and Phelps et al 2005, 2003). A particular interest of our work has been how HDM2 and HDMX protein synthesis is controlled in response to cell-signalling pathways in different cell types, and how this affects p53 function in these cells.
Role of CtBP transcriptional repressors in cancer cell proliferation and survival
In common with p53, CtBP1 and CtBP2 proteins were discovered through their physical association with a viral oncoprotein. We have shown that CtBPs also interact with HDM2 protein, and can consequently regulate p53 function (Mirnezami et al, 2003). The main function of CtBPs is as transcriptional co-repressors. They are involved in a range of cellular processes, depending upon the transcriptional repressor that recruits them to DNA, and they suppress the transcription of genes that cause apoptosis (reviewed in Bergman et al, 2006a). CtBP activity is modified by UV radiation and glycolytic metabolism, suggesting that CtBPs regulate cell survival in response to cellular stress. From 2004 The Breast Cancer Campaign has funded work in our laboratory to study the role of CtBPs in breast cancer. Our studies have progressed from studies of the basic mechanisms whereby CtBPs control breast cancer proliferation and survival (Birts et al 2011 and Bergman et al 2009, 2006a) to their impact on the response to current chemotherapies (Birts et al 2010) to the demonstration that CtBPs are themselves a therapeutically tractable potential molecular target for cancer therapy (Birts et al 2013). Our group was named Breast Cancer Campaign “Team of the Year 2011” on the basis of this work.
Antibody Effector Functions
Monoclonal antibodies (mAb) have become established in the treatment of a variety of malignancies - transforming patient outcomes. Despite this undoubted impact, responses remain variable and their mechanisms of action and of tumour resistance are controversial. Our research is focussed on understanding these complex processes using a variety of complementary models and systems to better inform antibody selection, design and clinical application.