Dynamic profiling of estrogen receptor and epidermal growth factor signaling in the uteri of genistein- and estrogen-treated rats

The pharmacokinetics and time course actions of the soy isoflavone, genistein, and estradiol benzoate (EB) on sex steroid and growth factor signaling were compared in the rat uterus. Following one s.c. injection of 500 mg genistein/kg BW or 500 μg EB/kg BW, AUC for genistein was 20171.8 ng h/ml and was 15.7 ng h/ml for estradiol-17-β. Estrogen receptor-α (ER-α) decreased within 2 h of genistein or EB treatment, returning to basal levels within 24 and 48 h, respectively. In response to genistein and EB, progesterone receptors (PRs) A and B increased between 16 and 24 h, with a significant increase at 24 and 48 h. Epidermal growth factor receptor (EGFR) expression peaked 16 h after genistein or EB treatment, inversely correlating with extracellular regulating kinase (ERK) phosphorylation. These effects were inhibited by antiestrogen pretreatment, demonstrating a requirement for ER. At 16 h, uterine weight, epithelial cell height, and cell proliferation increased. While EGFR levels increased, phosphorylated EGFR was not altered. Reduced phosphorylation of downstream kinases corresponded with decreased stromal phosphorylated-ERK (P-ERK) immunolabeling, suggesting signal attenuation. Dynamic profiling of sex steroid receptors and EGF signaling molecules suggest a similar mechanism of action for genistein and EB in the uterus, albeit at approximately 1000-fold concentration.