Effects of estrogen on breast cancer development: Role of estrogen receptor independent mechanisms
Corresponding Author
Wei Yue
Department of Medicine, University of Virginia Health System, Charlottesville, Virginia
Tel.: 434-924-0399, Fax: 434-924-1284
Division of Endocrinology and Metabolism, University of Virginia, P.O. Box 801416, Charlottesville, VA 22908Search for more papers by this authorJi-Ping Wang
Department of Medicine, University of Virginia Health System, Charlottesville, Virginia
Search for more papers by this authorYuebai Li
Department of Medicine, University of Virginia Health System, Charlottesville, Virginia
Search for more papers by this authorPing Fan
Department of Medicine, University of Virginia Health System, Charlottesville, Virginia
Search for more papers by this authorGuijian Liu
Department of Medicine, University of Virginia Health System, Charlottesville, Virginia
Search for more papers by this authorNan Zhang
Department of Medicine, University of Virginia Health System, Charlottesville, Virginia
Search for more papers by this authorMark Conaway
Department of Public Health Sciences, University of Virginia Health System, Charlottesville, Virginia
Search for more papers by this authorHongkun Wang
Department of Public Health Sciences, University of Virginia Health System, Charlottesville, Virginia
Search for more papers by this authorKenneth S. Korach
Receptor Biology Section, Laboratory of Reproductive and Developmental Toxicology, National Institutes of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina
Search for more papers by this authorWayne Bocchinfuso
Receptor Biology Section, Laboratory of Reproductive and Developmental Toxicology, National Institutes of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina
Search for more papers by this authorRichard Santen
Department of Medicine, University of Virginia Health System, Charlottesville, Virginia
Search for more papers by this authorCorresponding Author
Wei Yue
Department of Medicine, University of Virginia Health System, Charlottesville, Virginia
Tel.: 434-924-0399, Fax: 434-924-1284
Division of Endocrinology and Metabolism, University of Virginia, P.O. Box 801416, Charlottesville, VA 22908Search for more papers by this authorJi-Ping Wang
Department of Medicine, University of Virginia Health System, Charlottesville, Virginia
Search for more papers by this authorYuebai Li
Department of Medicine, University of Virginia Health System, Charlottesville, Virginia
Search for more papers by this authorPing Fan
Department of Medicine, University of Virginia Health System, Charlottesville, Virginia
Search for more papers by this authorGuijian Liu
Department of Medicine, University of Virginia Health System, Charlottesville, Virginia
Search for more papers by this authorNan Zhang
Department of Medicine, University of Virginia Health System, Charlottesville, Virginia
Search for more papers by this authorMark Conaway
Department of Public Health Sciences, University of Virginia Health System, Charlottesville, Virginia
Search for more papers by this authorHongkun Wang
Department of Public Health Sciences, University of Virginia Health System, Charlottesville, Virginia
Search for more papers by this authorKenneth S. Korach
Receptor Biology Section, Laboratory of Reproductive and Developmental Toxicology, National Institutes of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina
Search for more papers by this authorWayne Bocchinfuso
Receptor Biology Section, Laboratory of Reproductive and Developmental Toxicology, National Institutes of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina
Search for more papers by this authorRichard Santen
Department of Medicine, University of Virginia Health System, Charlottesville, Virginia
Search for more papers by this authorAbstract
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.
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