Effects of estrogen on breast cancer development: Role of estrogen receptor independent mechanisms

Development of breast cancer involves genetic factors as well as lifetime exposure to estrogen. The precise molecular mechanisms whereby estrogens influence breast tumor formation are poorly understood. While estrogen receptor α (ERα) is certainly involved, nonreceptor mediated effects of estradiol (E₂) may also play an important role in facilitating breast tumor development. A “reductionist” strategy allowed us to examine the role of ERα independent effects of E₂ on mammary tumor development in ERα knockout (ERKO) mice bearing the Wnt‐1 oncogene. Exogenous E₂ “clamped” at early follicular and midluteal phase levels (i.e., 80 and 240 pg/ml) accelerated tumor formation in a dose‐related fashion in ERKO/Wnt‐1 animals (p = 0.0002). Reduction of endogenous E₂ by oophorectomy (p < 0.001) or an aromatase inhibitor (AI) (p = 0.055) in intact ERKO/Wnt‐1 animals delayed tumorigenesis as further evidence for an ER‐independent effect. The effects of residual ERα or β were not involved since enhancement of tumor formation could not be blocked by the antiestrogen fulvestrant. 17α‐OH‐E₂, a metabolizable but ER‐impeded analogue of E₂ stimulated tumor development without measurable uterine stimulatory effects. Taken together, our results suggest that ER‐independent actions of E₂ can influence breast tumor development in concert with ER dependent effects. These observations suggest 1 mechanism whereby AIs, which block E₂ synthesis, would be more effective for breast cancer prevention than use of antiestrogens, which only block ER‐mediated effects.