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

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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.