Defining Mechanisms of Hormone Therapy Breast Cancer Risk Reduction and Biomarkers of Response

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When breast tissue undergoes x-ray (i.e. a mammogram), the fatty component appears black whilst the areas containing the glandular tissue appear white. Mammograms with a large proportion of white are said to have high mammographic density (high MD). This is largely due to large amounts of supporting material in the breast called stroma. Over recent years it has become apparent that having high MD confers a significant increased risk for the development of breast cancer, although the mechanism which confers this increased risk is not understood.High MD is a common finding in the mammograms of women in the UK and globally. Therefore, interventions targeted towards reducing MD have the potential to benefit large numbers of women.Recently it has been shown that the anti-oestrogen drug tamoxifen can reduce the risk of developing breast cancer when given to women with a strong family history. This reduction in risk corresponds to a reduction in MD. In addition, those women who show no reduction in breast density with tamoxifen treatment show no associated reduction in breast cancer risk, suggesting that the protective effect of this drug is mediated through reduction of MD.This project aims to build on these key observations to investigate how MD can be modulated to establish markers that may help us predict which women will be protected or benefit from anti-oestrogen treatments. This project will look at the effect of tamoxifen and aromatase inhibitors on human breast tissues. At Barts Cancer Institute we routinely consent patients undergoing surgery for donation of breast tissue not needed for diagnosis to be used in research. We will use these samples in our research to investigate the mechanisms by which anti-oestrogens exert their protective effect. Stromal cells will be treated with tamoxifen and an aromatase inhibitor and the effect on a series of molecules potentially involved will be assessed. We will also validate the results on samples taken prospectively.The importance of this project is that by understanding the pathways contributing to high MD we will better understand the factors leading to development of breast cancer and this will help devise new ways of preventing it. Therefore we anticipate the results of this research will particularly benefit women who are at high risk of developing breast cancer.The results from this research may also assist doctors in predicting which of these high risk women will respond well to treatments such as tamoxifen and aromatase inhibitors, that are aimed at reducing MD, and critically, identify those women who will not respond. This will mean that they will only be prescribed to women who are likely to have a good response to the treatment. Those that are unlikely to respond well will be spared some of the treatment associated side effects.