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

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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.