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

确定激素治疗降低乳腺癌风险的机制和反应生物标志物

• 批准号: MR/M019039/1
• 负责人: Kathryn Hawkesford
• 金额: $ 28.39万
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM019039%2F1
• 关键词: Defining; Mechanisms; Hormone; Therapy; Breast

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.

当乳房组织经历X射线（即乳房X线照片）时，脂肪成分呈现黑色，而包含腺体组织的区域呈现白色。白色比例大的乳房X线片被认为具有高乳房X线密度（高MD）。这在很大程度上是由于乳房中有大量的支持物质，称为基质。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是英国和全球女性乳房X光片中的常见发现。因此，针对减少MD的干预措施有可能使大量妇女受益。最近，有研究表明，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。这种风险的降低对应于MD的降低。此外，这些妇女谁显示没有减少乳腺密度与他莫昔芬治疗显示没有相关的减少乳腺癌的风险，这表明这种药物的保护作用是通过介导的MD减少。该项目旨在建立在这些关键的观察，以调查如何MD可以调制建立标记，可以帮助我们预测哪些妇女将得到保护或受益于抗雌激素治疗。这个项目将着眼于他莫昔芬和芳香化酶抑制剂对人类乳腺组织的影响。在Barts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腺组织用于研究。我们将使用这些样本在我们的研究中，以探讨抗雌激素发挥其保护作用的机制。将用他莫昔芬和芳香酶抑制剂处理基质细胞，并评估对一系列可能涉及的分子的影响。我们还将验证前瞻性样本的结果。该项目的重要性在于，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展的因素，这将有助于制定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益于乳腺癌高危女性。这项研究的结果也可以帮助医生预测哪些高危妇女将对治疗反应良好，如他莫昔芬和芳香化酶抑制剂，旨在减少MD，并关键是，确定那些妇女谁不会响应。这将意味着它们将只被开给那些可能对治疗有良好反应的女性。那些不太可能反应良好的人将免于一些治疗相关的副作用。