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 alpha (ERalpha) is certainly involved, non−receptor mediated effects of estradiol (E(2)) may also play an important role in facilitating breast tumor development. A "reductionist" strategy allowed us to examine the role of ERalpha independent effects of E(2) on mammary tumor development in ERalpha knock out (ERKO) mice bearing the Wnt−1 oncogene. Exogenous E(2) "clamped" at early follicular and mid−luteal 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 E(2) by oophorectomy (p<0.001) or an aromatase inhibitor (p=0.055) in intact ERKO/Wnt−1 animals delayed tumorigenesis as further evidence for an ER−independent effect. The effects of residual ERalpha or beta were not involved since enhancement of tumor formation could not be blocked by the anti−estrogen fulvestrant. 17alpha−OH−E(2), a metabolizable but ER−impeded analogue of E(2)stimulated tumor development without measurable uterine stimulatory effects. Taken together, our results suggest that ER−independent actions of E(2) can influence breast tumor development in concert with ER dependent effects. These observations suggest one mechanism whereby aromatase inhibitors, which block E(2) synthesis, would be more effective for breast cancer prevention than use of anti−estrogens which only block ER−mediated effects. (c) 2010 UICC.

PMID: 20104523 [PubMed − as supplied by publisher] Source: National Library of Medicine.