Estetrol prevents estradiol-induced precancerous cell proliferation in mice

Estradiol (E2) is one of estrogens and involved in breast tumorigenesis. Estetrol (E4), another estrogen, is synthesized in the fetoplacental unit and circulates in the mother's body only during pregnancy. Although E4 exhibits anti-estrogenic activity in the presence of E2 in malignant breast cancer cell culture, E4 function in breast tumorigenesis in vivo has not been fully explored. This study used a mouse early breast cancer induction model system, and revealed the preventive effect of E4 on E2-induced mammary dysplasia formation. E4 reduced E2-induced abnormal mammary epithelial cell proliferation. Moreover, this study shows that E2 activates IL-1 receptor signaling through downregulation of IL-1 receptor antagonist gene expression in mammary epithelial cells. E4 administration prevented E2-induced IL-1 receptor signaling, and in the onset of dysplasia formation, a reduction in IL-1 signaling reduced abnormal mammary epithelial cell proliferation. After dysplasia formation, E4 administration reduced the frequency of dysplasia, suggesting that E4 restores mammary tissue to normal. This study first reveals the molecular mechanism of E4 in early breast cancer prevention.