Estrogen and insulin synergistically promote endometrial cancer progression via crosstalk between their receptor signaling pathways

OBJECTIVE: Despite evidence that estrogens and insulin are involved in the development and progression of many cancers, their synergistic role in endometrial carcinoma (EC) has not been analyzed yet. METHODS: Here, we investigated how estrogens act synergistically with insulin to promote EC progression. Cell growth in vitro and in vivo, effects of estradiol and insulin on apoptosis and cell cycle distribution, and expression and activation of estrogen receptor (ER), insulin receptor (InsR), and key proteins in the PI3K and MAPK pathways were examined after combined stimulation with estradiol and insulin. RESULTS: Compared to EC cells treated with estradiol or insulin alone, those treated with both estradiol and insulin exhibited stronger stimulation. Estradiol significantly induced phosphorylation of InsR-β and IRS-1, whereas insulin significantly induced phosphorylation of ER-α. In addition, treatment with both insulin and estradiol together significantly increased the expression and phosphorylation of Akt, MAPK, and ERK. Notably, InsR-β inhibition had a limited effect on estradiol-dependent proliferation, cell cycle, and apoptosis, whereas ER-α inhibition had a limited insulin-dependent effect, in EC cell lines. Insulin and estradiol individually and synergistically promoted EC xenograft growth in mice. CONCLUSIONS: Estrogen and insulin play synergistic roles in EC carcinogenesis and progression by activating InsR-β and ER-α, promoting a crosstalk between them, and thereby resulting in the activation of downstream PI3K/Akt and MAPK/ERK signaling pathways.