Estrogen receptors and the estrone hypothesis in relation to endometrial and breast cancer

Estrogen binding to normal and abnormal human endometrial cytoplasmic and nuclear receptors has been demonstrated by sucrose density-gradient ultracentrifugation. Estrone binds to cytoplasmic receptor, and the resulting complex is transferred into the nucleus, suggesting that estrone is an active estrogen in human endometrium. Estriol at equimolar concentrations effectively competes with estrone for binding to immature rat uterine cytoplasmic receptor, whereas much higher concentrations are required for effective competition with estradiol. Together with our extensive studies demonstrating the exclusive production of estrone by anovulatory subjects having a high risk for development of endometrial or breast cancer, these results have led to the formulation of the "estrone hypothesis." This hypothesis suggests that unopposed exposure of target tissues to estrone may be a causal factor in the development of cancer. The postulated "protective effect" of estriol in low cancer incidence populations (Japanese) and the beneficial effects of pregnancy on cancer risk can be explained on the basis of these findings.