Dr James Flanagan
I completed my PhD in 2002 at the Queensland Institute of Medical Research in Brisbane, Australia, and have pursued postdoctoral work in Cancer Genetics (QIMR, Australia), Epigenetics (University of Toronto, Canada) and Cancer Epigenetics (UCL, UK). In 2009 I was awarded a Breast Cancer Campaign Scientific Fellowship which allowed me to move to Imperial College as a new group leader. Following this fellowship I was appointed to Senior Lecturer in Epigenetics in October 2014.
Our recent work has focussed on the hypothesis that epigenetic variation may be a driver of cancer risk whether by inherent variation between individuals or as a mediator of other cancer risk factors that we accumulate throughout our lives. Importantly, epigenetic risk may be reversible and this new CRUK PhD studentship project, undertaken by Caitriona Tyndall, aims to investigate the epigenetic consequences of a drug, metformin, which is used for diabetic patients and is believed to reduce breast cancer risk. In collaboration with Dr Marc Gunter (IARC, Lyon, France) this project will combine lab based experiments with population based studies.
What is this project about?
Breast cancer is the most commonly diagnosed cancer in the UK contributing to over 49,000 cases in 2011 and 7% of total cancer-related deaths. While survival rates for breast cancer are improving, with 5-year survival rates for 2011 at 86%, it is still a considerable public health burden. To reduce this burden, research in recent years has aimed to develop and improve methods to predict and prevent breast cancer by understanding how breast cancer starts.
There are many risk factors associated with breast cancer including, age, menopausal status, smoking and obesity. A risk factor that is not often studied is type II diabetes mellitus (T2DM). Increased insulin and glucose levels have been shown to activate cancer pathways and metformin, a drug typically used to treat T2DM, has been shown to reduce breast cancer incidence by 60%, potentially by re-sensitizing breast cells to insulin. We will investigate epigenetic patterns that dictate how much of a gene is made into proteins thereby regulating gene expression. Changes in epigenetic patterns are a common hallmark of cancer progression and changed epigenetic patterns have been shown to be effective biomarkers of breast cancer risk.
This study aims to investigate the effect of insulin, glucose and metformin treatment on normal breast cells in culture and identify ‘signatures of effect’ through genome-wide methylation arrays. We will use this knowledge gained from cell culture to investigate existing population cohort data to determine if signatures derived from cell culture can be suitable indicators of breast cancer risk. This study will determine if markers of poor metabolic health, insulin and glucose, and T2DM drugs such as metformin can alter epigenomes of normal breast epithelial cells and if these provide a mechanism for why they might be reducing breast cancer susceptibility.
How does this project align with the rest of our research?
Our laboratory focuses on epigenetic mechanisms of breast and ovarian cancer with expertise in molecular epigenetics, epigenomic profiling and cell culture. Other current projects are aiming to identify an epigenetic signature in blood DNA of lifetime oestrogen exposure in relation to breast cancer risk; to investigate DNA repair driven epigenetic changes in response to platinum based chemotherapy; and to conduct genome-wide analyses and cell culture based validation of environmental driven epigenetic changes due to air pollution and tobacco smoking.