Role of estrogen receptor beta in cancer prevention by dietary indole-3-carbinol

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DESCRIPTION (provided by applicant): The long-term goal of this research is to develop a better understanding of how dietary phytochemicals can influence human health and disease, lndole-3-carbinol (I3C), a key active component of cruciferous vegetables, has been shown to be a remarkably effective cancer blocking agent by reducing risk of lung, colon, breast and skin cancer. There is great concern that fetal exposure to environmental chemicals during pregnancy, such as smoke carcinogens, could be linked to childhood and young adult cancers. A recent study using a transplacental mouse cancer model showed that maternal consumption of I3C coincident with carcinogen exposure markedly decreased offspring mortality due to aggressive thymic lymphoma as well as lung tumor multiplicity in 10 month-old offspring. The chemopreventive properties of I3C can involve multiple mechanisms of action, including interaction with the aryl hydrocarbon receptor (AhR) and the estrogen receptor (ER). In this prior transplacental cancer study, the chemopreventive property of I3C was not dependent on the AhR. Thus, while I3C is an effective chemoprotective compound transplacentally, the mechanism by which it exerts its protective effects is unknown. To address this critical knowledge gap, the therapeutic efficacy of I3C in prevention of cancer in offspring exposed in utero to the environmental carcinogen dibenzo[a,l]pyrene (DBP) will be evaluated using an ERbeta knockout mouse model. ERbeta is the major ER subtype expressed in the thymus and lung. The working hypothesis is that protection by I3C against DBP-induced transplacental carcinogenesis requires ERbeta expression. The experimental approach employed to test this hypothesis consists of a 10 month transplacental cancer study utilizing specific dietary protocols to test the efficacy of I3C as a chemopreventive agent during tumor initiation and tumor promotion phases in both ERbeta positive and negative gestating environments. Endpoints to be evaluated in offspring include lymphoma-dependent mortality, lung and liver tumor outcome, morphometric data and global gene expression profiles of tumors. The fetus is a sensitive target for environmental compounds, and a significant portion of lifetime exposure to chemical carcinogens occurs during gestation and throughout breast feeding. Evidence suggests that maternal consumption of certain vegetables or plant-derived compounds, such as indole-3- carbinol, during pregnancy can prevent childhood and adult cancers in offspring. However, the current lack of understanding of the mechanisms by which indole-3-carbinol exerts its cancer blocking effects to the fetus raises questions about its possible utility as a preventive and/or therapeutic agent for human cancer.