Almost every cell in the body is responsive to stress through release of hormones termed stress hormones and the response to stress can differ depending on the type and duration of the stressor. Acute stress can facilitate a “fight or flight response” and aid survival, chronic long-term stress on the other-hand with the persistent release of stress hormones has been shown to be detrimental to health. We are now beginning to understand how this stress hormone response impacts important processes such as DNA repair and cell proliferation processes in breast cancer. However, it is not known what epigenetic changes stress hormones induce in breast cancer. Epigenetic mechanisms include modification of DNA and histones within chromatin that may be involved in governing the transcriptional processes in cancer cells in response to changes by endogenous stress hormones. The contribution of endogenous acute or long term exposure of glucocorticoid stress hormones, and exogenous glucocorticoids to methylation patterns in breast cancer tissues with different aetiologies is highly innovative and remains to be evaluated. In vitro and in vivo models were developed to investigate the epigenetic modifications and their contribution to breast cancer progression and aetiology. As ageing is a risk factor for breast cancer and is highly affected by epigenetic modifications, an ageing in vivo model was developed to examine the influence of stress and ageing on epigenetic regulation in breast cancer. Treating a panel of triple negative breast cancer cell lines with the primary glucocorticoid hormone cortisol resulted in epigenetic alteration characterised by downregulation of DNMT1, loss of methylation on promoter regions of tumour suppressor genes including ESR1, and loss of methylation on LINE-1 repetitive element used as a surrogate marker for global methylation. This was verified in vivo in MDA-MB-231 xenografts; the model verified the loss of methylation on ESR1 promoter, and subsequent increase in ESR1 expression in primary tumours in mice subjected to restraint stress. With regards to the influence of ageing, a syngeneic breast cancer mouse model was developed; older mice exhibited a decrease in DNMT1 in breast cancer tumours with age increase from 3-18 months. Our study highlights that DNA methylation landscape in breast cancer can be altered in response to stress and glucocorticoid treatment. The study also suggests that stress and ageing can influence epigenetic modifications in breast cancer.
|Date of Award||Feb 2020|
|Supervisor||Melanie Flint (Supervisor), Marcus Allen (Supervisor) & Mark Yeoman (Supervisor)|