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

当乳房组织接受X光检查(即乳房X光检查)时，脂肪成分显示为黑色，而包含腺体组织的区域显示为白色。白色比例较大的乳房X光照片据说具有高密度(高MD)。这在很大程度上是由于乳房中有大量被称为基质的支持物质。近年来，很明显，高MD会显著增加患乳腺癌的风险，尽管导致这种风险增加的机制尚不清楚。高MD在英国和全球女性的乳房X光检查中是常见的发现。因此，旨在减少MD的干预措施有可能使大量妇女受益。最近的研究表明，抗雌激素药物他莫昔芬可以降低有强烈家族史的妇女患乳腺癌的风险。这种风险的降低与MD的减少相对应。此外，那些使用他莫昔芬治疗乳房密度没有下降的女性并没有表现出乳腺癌风险的相关降低，这表明这种药物的保护作用是通过减少MD来实现的。这个项目旨在以这些关键观察为基础，研究如何调节MD来建立标记，这些标记可能有助于我们预测哪些女性将从抗雌激素治疗中得到保护或受益。这个项目将观察他莫昔芬和芳香酶抑制剂对人类乳房组织的影响。在巴茨癌症研究所，我们通常同意接受手术的患者捐赠诊断不需要的乳房组织用于研究。我们将在我们的研究中使用这些样本来研究抗雌激素发挥保护作用的机制。基质细胞将用他莫昔芬和芳香酶抑制剂处理，并将评估对一系列潜在涉及的分子的影响。这项计划的重要之处，是通过了解导致高MD的途径，我们将更好地了解导致乳腺癌发生的因素，这将有助于设计出预防乳腺癌的新方法。因此，我们预计这项研究的结果将特别有利于那些患乳腺癌的高危女性。这项研究的结果还可能有助于医生预测这些高危女性中哪些人对旨在减少MD的他莫昔芬和芳香酶抑制剂等治疗反应良好，并关键是确定哪些女性不会有反应。这将意味着它们只会被开给对治疗有良好反应的女性。那些不太可能有很好反应的人将免除一些与治疗相关的副作用。

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.