Lifelong exposure to dietary isoflavones-potential impact on carcinogenesis of the mammary gland

终生接触膳食异黄酮——对乳腺癌发生的潜在影响

• 批准号: 191831814
• 负责人: Dr. Clarissa Gerhäuser
• 金额: --
• 依托单位: Abteilung Epigenomik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2011
• 资助国家: 德国
• 起止时间: 2010-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/191831814?language=en
• 关键词: Lifelong; exposure; dietary; isoflavones; potential

Molecular and cellular functions of isoflavones (IF) and their relation in menopausal health are controversially discussed and therefore attained a considerable public awareness. Whereas lifelong or even multigenerational consumption of a IF rich diet seems to be preventive regarding menopausal complications and the development of hormone dependent cancers, a supplementation with fortified IF preparations at an advanced age eventually poses some risks towards hormonal carcinogenesis. We aim to contribute to close a considerable knowledge gap on the molecular mode of function of IF, particularly in longterm (lifelong) applications and in relation to breast cancer. In a recent study of our laboratory we investigated if and how lifelong dietary exposure to IF impacts on the physiology of estrogen dependent target organs. One of the major findings was that lifelong dietary exposure to IF considerably modulates estrogen responsiveness in target organs. With the proposal presented here we aim to adopt our established longterm dietary exposure protocol for IF to the ACI rat model of estrogen (E2)-induced breast cancer and to explore how a modification of estrogen responsiveness by IF exposure will impact on the carcinogenesis of the mammary gland using the specific features of E2 induced breast cancer in ACI rats. Besides tumor specific endpoints, mammary gland morphology, IF dependent gene signatures, epigenetic changes as well as changes in the steroid metabolizing capacity of the tissue will be monitored at different critical periods of sexual maturation of the animals. We hypothesize that we will be able to show if and how early molecular changes in developing breast tissue will determine breast cancer susceptibility later in life. The knowledge acquired will be crucial for the evaluation of potential prevention strategies.

雌激素的分子和细胞功能及其与绝经期健康的关系一直备受争议，并因此获得了相当大的公众意识。尽管终身或甚至多代食用富含IF的饮食似乎可以预防更年期并发症和激素依赖性癌症的发生，但在高龄时补充强化IF制剂最终会对激素致癌产生一定风险。我们的目标是有助于缩小相当大的知识差距的分子功能模式的IF，特别是在长期（终身）的应用和乳腺癌。在我们实验室最近的一项研究中，我们调查了终身膳食暴露于IF是否以及如何影响雌激素依赖性靶器官的生理学。其中一个主要发现是，终身膳食暴露于IF大大调节靶器官的雌激素反应。与这里提出的建议，我们的目标是通过我们建立的长期饮食暴露协议的IF的雌激素（E2）诱导的乳腺癌的ACI大鼠模型，并探讨如何修改雌激素的反应性IF曝光将影响乳腺癌的发生，使用E2诱导的乳腺癌在ACI大鼠的具体功能。除了肿瘤特异性终点外，还将在动物性成熟的不同关键时期监测乳腺形态、IF依赖性基因特征、表观遗传变化以及组织类固醇代谢能力的变化。我们假设，我们将能够显示是否以及如何在发育中的乳腺组织的早期分子变化将决定乳腺癌的易感性在以后的生活。所获得的知识对于评价潜在的预防战略至关重要。