Influence of tissue-specific isoflavone profiles on generation, activation and action of 17â-estradiol in the human and rat mammary gland

类固醇激素17β-雌二醇在乳腺癌的发生发展中起着至关重要的作用：它控制着细胞的增殖和分化，也是诱变性醌类化合物的前体。我们实验室最近的体外数据显示，异黄酮与参与这两个过程的细胞信号通路相互作用。因此，我们项目的目标是阐明(I)组织特异性异黄酮谱对成人绝经前和绝经后乳腺17种β-雌二醇代谢产物谱和局部雌激素暴露的生物标志物的影响；(Ii)遗传毒性应激以及参与细胞增殖和分化的细胞内和细胞间信号转导的后果；(Iii)DNA甲基化在调节乳腺这些过程中的作用，并确定外周血单核细胞DNA甲基化的生物标志物；(Iv)血液中异黄酮谱对局部异黄酮性暴露的意义；(V)在人和大鼠乳腺中观察到的可比性；(Vi)在西方和亚洲异黄酮类暴露的情况下17β-雌二醇的激活；(Vii)肿瘤形成过程对当地17β-雌二醇代谢物分布的影响。在Kulling博士、Gerhäuser博士和Vollmer博士的密切合作下，一项针对绝经前和绝经后妇女在乳房缩小手术前摄入具有特征异黄酮谱的大豆提取物的人类干预研究将与17β-雌二醇诱导肿瘤形成的大鼠模型相补充，以实现这一目标。我们的项目不仅将为IF在乳腺中的作用模式提供新的见解，还将有助于理解17β-雌二醇依赖的乳腺肿瘤启动的基本机制。

The steroid hormone 17β-estradiol plays a crucial role in the development of breast cancer: It controls cell proliferation and differentiation and constitutes also a precursor of mutagenic quinones. Recent in vitro data from our lab showed that isoflavones interact with cellular signaling pathways involved in both processes. Therefore, the goal of our project is to elucidate the (i) impact of tissue-specific isoflavone profiles on 17β- estradiol metabolite profiles and biomarker for local quinone estrogen exposure in adult human pre- and postmenopausal mammary gland; (ii) consequences of (i) for genotoxic stress and intra- and intercellular signaling involved in cell proliferation and differentiation; (iii) role of DNA methylation in the regulation of these processes in the mammary gland and identify biomarkers for DNA methylation in peripheral blood monocytes; (iv) significance of isoflavone profiles in blood for local isoflavone exposure; (v) comparability of the observations in human and rat mammary gland; (vi) 17β-estradiol activation in the Western and Asian isoflavone exposure scenario; (vii) impact of the tumorigenic process on local 17β-estradiol metabolite profiles. In close cooperation with Dr. Kulling, Dr. Gerhäuser, and Dr. Vollmer, a human intervention study with pre- and postmenopausal women consuming a soy extract with characteristic isoflavone spectrum prior to mammary reduction surgery will be complemented by a rat model of 17β-estradiol induced tumorigenesis to achieve this goal. Our project will not only provide novel insight into the mode of action of IF in the mammary gland but also contribute to the understanding of the basic mechanisms involved in 17β-estradiol dependent tumor initiation in the mammary gland.