In the DFG-funded project we have demonstrated that tissue-selective responsiveness to treatment with estrogen receptor ligands in female rats is strongly affected by lifelong exposure to isoflavones (IF). Lifelong IF intervention reduced the responsiveness of the breast, whereas the responsiveness of the uterus was induced. The underling molecular mechanisms are still unclear. So far, it is also not known whether estrogen sensitivity of non classical estrogen-sensitive tissues, such as the intestine, bone and adipose tissue, is also modified by lifelong IF exposure. Ongoing studies have been limited to females; effects on males have not been investigated so far.Based on these previous investigations, the major aims of the proposed research project are:a.) Further investigation of the molecular mechanisms involved in the modulation of tissue-selective responsiveness of estrogen-sensitive tissues by isoflavones. b.) High-fat diet but also isoflavones are discussed to modulate the susceptibility of estrogen-sensitive tissue, especially the breast, to develop cancer. Therefore we will investigate the combined effects of high-fat diet and isoflavones on the responsiveness of estrogen-sensitive tissues and isoflavone metabolism.c.) Adiposity is a known risk factor for postmenopausal breast cancer. Consequently we will determine the effects of lifelong but also acute exposure to isoflavones on the development of adiposity in a diet-driven rat animal model of adiposity induction.
Soy IF have also been reported to affect epigenetic mechanisms, including DNA methylation. Since epigenetic control of gene expression has important functions during development and is critical for cell type specific gene expression, we hypothesized that lifelong exposure to soy IF might lead to "reprogramming" of the mammary gland (MG) and consequently reduced breast cancer susceptibility. Our aim was to clarify whether lifelong exposure to IF starting in utero would influence epigenetic mechanisms - especially DNA methylation patterns – in MG and whether these epigenetic modifications would influence estrogen-induced mammary tumorigenesis in ACI rats. For a comparison of an “Asian” and “Western” exposure scenario, DNA methylation changes in response to a short-term IF intervention were assessed in rat and human mammary glands. In summary, we generated unique novel information on isoflavone (IF)-induced genome-wide epigenetic regulation in breast tissue in humans and rats in vivo. Our data indicate differential response to soy IF depending on the dose, timing and duration of exposure.