Genistein: Breast Cancer Protection and In Vivo Mechanisms of Action

We have hypothesized that early exposure to soy confers lifetime protection against breast cancer. This was investigated in Sprague Dawley CD rats exposed neonatally and prepubertally to injections of pharmacological doses of genistein and perinatally to physiological doses of genistein in the diet. These treatments resulted in a reduced number of dimethylbenz[a]anthracene (DMBA)-induced mammary tumors in the adults. The initial effect of early exposure to genistein was to upregulate the epidermal growth factor (EGF) signaling pathway and to downregulate transforming growth factor-β (TGF-β) expression in young animals. These actions enhanced cell differentiation and resulted in reduced EGF-receptor expression in terminal end buds of adults. These differentiated cells are less proliferative and less susceptible to carcinogenesis. Bioavailability studies revealed that 25 and 250 mg genistein per kilogram of body weight diet resulted in total genistein concentrations of 54 and 1810 pmol/ml in serum of prepubertal rats. Genistein is demonstrated to be bioavailable to the mammary gland in postnatal rats. Prenatal genistein in the diet (250 mg/kg) did not protect against DMBA-induced mammary cancer or result in significant toxicity to the F₁ female reproductive tract. Prenatal exposure to genistein via the diet yielded only 43 pmol total genistein per milliliter of blood in the fetus. We conclude that in utero exposure to genistein via the diet does not protect against mammary cancer or cause toxicity because conjugated genistein cannot cross the placental barrier. Our results demonstrate in the rat that postnatal exposure to physiological concentrations of genistein in the diet is a safe and effective means of programming against chemically induced mammary cancer.