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

<jats:title>Abstract</jats:title><jats:p>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 (<jats:italic>E</jats:italic><jats:sub>2</jats:sub>) 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 <jats:italic>E</jats:italic><jats:sub>2</jats:sub> on mammary tumor development in ERα knockout (ERKO) mice bearing the Wnt‐1 oncogene. Exogenous <jats:italic>E</jats:italic><jats:sub>2</jats:sub> “clamped” at early follicular and midluteal phase levels (<jats:italic>i.e</jats:italic>., 80 and 240 pg/ml) accelerated tumor formation in a dose‐related fashion in ERKO/Wnt‐1 animals (<jats:italic>p</jats:italic> = 0.0002). Reduction of endogenous <jats:italic>E</jats:italic><jats:sub>2</jats:sub> by oophorectomy (<jats:italic>p</jats:italic> < 0.001) or an aromatase inhibitor (AI) (<jats:italic>p</jats:italic> = 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‐<jats:italic>E</jats:italic><jats:sub>2</jats:sub>, a metabolizable but ER‐impeded analogue of <jats:italic>E</jats:italic><jats:sub>2</jats:sub> stimulated tumor development without measurable uterine stimulatory effects. Taken together, our results suggest that ER‐independent actions of <jats:italic>E</jats:italic><jats:sub>2</jats:sub> can influence breast tumor development in concert with ER dependent effects. These observations suggest 1 mechanism whereby AIs, which block <jats:italic>E</jats:italic><jats:sub>2</jats:sub> synthesis, would be more effective for breast cancer prevention than use of antiestrogens, which only block ER‐mediated effects.</jats:p>