Estradiol-17β regulates mouse uterine epithelial cell proliferation through insulin-like growth factor 1 signaling

Estradiol-17 beta(E-2) causes cell proliferation in the uterine epithelium of mice and humans by signaling through its transcription factor receptor a (ER alpha). In this work we show that this signaling is mediated by the insulin-like growth factor 1 receptor (IGF1R) expressed in the epithelium, whose activation leads to the stimulation of the phosphoinositide 3-kinase/protein kinase B pathway leading to cyclin 1311 nuclear accumulation and engagement with the canonical cell cycle machinery. This cyclin D1 nuclear accumulation results from the inhibition of glycogen synthase kinase 3 beta (GSK3 beta) activity caused by an inhibitory phosphorylation by protein kinase B. Once the IGF1 pathway is activated, inhibition of ER signaling demonstrates that it is independent of ER. Inhibition of GSK3 beta in the absence of E2 is sufficient to induce uterine epithelial cell proliferation, and GSK3 beta is epistatic to IGF1 signaling, indicating a linear pathway from E2 to cyclin D1. Exposure to E2 is the major risk factor for endometrial cancer, suggesting that downstream activation of this IGF1-mediated pathway by mutation could be causal in the progression to ER-independent tumors.