Timing of exposure and mammary cancer risk.

We have tested the hypothesis that timing of exposure to hormonally active chemicals can predetermine susceptibility for mammary cancer. TCDD, the most potent man-made xenobiotic, when given to pregnant rats resulted in the offspring being more susceptible to chemically induced mammary cancer as adults. On the other hand, genistein, the primary isoflavone component of soy, given in the diet during the prepubertal period, or the prepubertal and adult periods, protected against chemically induced mammary cancer. There was an inverse relationship between cancer susceptibility and mammary gland differentiation. The initial effect of early exposure to genistein was to up-regulate the EGF-signaling pathway and to enhance cell differentiation, resulting in reduced EGF-receptor expression in mammary terminal end buds of adults. Genistein has been shown to be bioavailable to the mammary gland in postnatal rats. Differentiation effects are believed to occur via an imprinting mechanism that determines the "blueprint" from which the mammary cells respond to future hormonal and/or xenobiotic exposure.