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

异黄酮类(IF)的分子和细胞功能及其与更年期健康的关系是有争议的讨论，因此获得了相当大的公众意识。虽然终生甚至几代人食用丰富的IF饮食似乎可以预防更年期并发症和激素依赖型癌症的发展，但在高龄补充强化IF制剂最终会带来一些激素致癌的风险。我们的目标是弥补在IF分子功能模式方面的相当大的知识差距，特别是在长期(终生)应用和与乳腺癌有关的方面。在我们实验室最近的一项研究中，我们调查了终身饮食暴露于IF是否以及如何影响雌激素依赖的靶器官的生理。其中一个主要发现是，终生饮食暴露于IF相当大程度上调节了靶器官的雌激素反应。通过这项建议，我们的目标是采用我们建立的雌激素(E2)诱导的ACI大鼠乳腺癌模型的IF长期膳食暴露方案，并利用雌激素诱导的ACI大鼠乳腺癌的特定特征，探讨IF暴露对雌激素反应性的改变如何影响乳腺的癌变。除了肿瘤特定的终点外，还将在动物性成熟的不同关键时期监测乳腺形态、依赖的基因特征、表观遗传学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展示发育中的乳腺组织的早期分子变化是否以及如何决定乳腺癌在以后的生活中的易感性。所获得的知识将对评估潜在的预防战略至关重要。

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.