Estrone-induced cell proliferation and differentiation in the mammary gland of the female Noble rat.

In this study we examined the influence of estrone on proliferation and differentiation in the mammary gland of female Noble rats. Estrone treatment increased proliferation in mammary epithelial cells at days 3 and 7, and peaked by day 11 of estrone exposure. In addition, estrone exposure altered cell cycle kinetics. Animals exposed to estrone for 11 days demonstrated a 9-fold increase in the cells in G1 phase and a 48-fold increase in the cells in S phase, compared to those of controls. Differentiation, measured by the degree of lobular maturation, was significantly increased in the treatment group by day 7 and continued to mature through day 21 post estrone implant. The appearance of the mammary glands in these animals approached the morphology normally found during pregnancy and lactation. In a subset of animals we examined the effects of a concurrent treatment with luteolin, a bioflavonoid which has been shown to inhibit estrone binding to type II estrogen receptors. Luteolin significantly reversed the effects of estrone treatment on both proliferation and differentiation in these animals. Changes in proliferation and cell cycle kinetics have been shown to lead to genetic instability, ultimately resulting in cell transformation. Our results indicated an increase in proliferative cells by > 2-fold and a perturbation in cell cycle kinetics from estrone exposure. These changes may play a role in the induction of estrone-induced mammary cancer in the Noble rat model. In addition, the anti-proliferative action of luteolin suggests that it may play a protective role in estrone-induced mammary carcinogenesis.