Breast cancer is one of the leading causes of human cancer. Chemically- induced mammary cancer in rats provides a model of susceptibility for the study of carcinogenesis in human mammary glands. Chemoprevention rather than cancer treatment is a preferred means of health promotion. Our goal is to identify an efficacious chemopreventive agent for human females inherently susceptible for mammary cancer. In this interactive R0l we propose to investigate a novel approach, chemoprevention via critical period(s) of development with a nutritional component of soy-based foods, i.e., genistein. Genistein is a phytoestrogen found in soy-based products, the latter having been associated with a 2 to 5-fold lower incidence of and death from breast cancer in women consuming soy products not only as adults, but also pre- and postnatally. Estrogens given either neonatally or just prior to carcinogen exposure have been shown to prevent mammary adenocarcinomas. Since genistein is a weak estrogen agonist/antagonist, we hypothesize that it will exert a chemopreventive effect via imprinting mechanisms and/or developmental maturation of the mammary when given neonatally. Our experiments will l) determine if biochemical imprinting during the neonatal period, or prepubertal exposure to genistein will reduce the incidence of dimethylbenz(a)anthracene- induced mammary adenocarcinomas, 2) if neonatal and prepubertal exposure to genistein will alter mammary cell differentiation (using mammary whole mounts) and proliferation (using PCNA/cyclin immunohistochemistry), and 3) if early genistein exposure will alter activation/detoxication mechanisms in the mammary. The latter will be assessed by measuring the rate of formation and persistence of carcinogen-DNA adducts as a means of determining the programming effect of genistein On initiation mechanisms of cancer.
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